WO2019063704A1 - Substituted 3-phenylquinazolin-4(3h)-ones and uses thereof - Google Patents

Substituted 3-phenylquinazolin-4(3h)-ones and uses thereof Download PDF

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WO2019063704A1
WO2019063704A1 PCT/EP2018/076287 EP2018076287W WO2019063704A1 WO 2019063704 A1 WO2019063704 A1 WO 2019063704A1 EP 2018076287 W EP2018076287 W EP 2018076287W WO 2019063704 A1 WO2019063704 A1 WO 2019063704A1
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diazabicyclo
compound
methyl
general formula
hydrogen atom
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PCT/EP2018/076287
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French (fr)
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Eloisa JIMENEZ NUNEZ
Julian BORISSOFF
Michael Hahn
Lisa Dietz
Fabienne Zdenka GAUGAZ
Eckhard Bender
Dieter Lang
Anja Giese
Kai Thede
Ludwig Zorn
Melissa BOULTADAKIS ARAPINIS
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Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft
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Publication of WO2019063704A1 publication Critical patent/WO2019063704A1/en

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention covers substituted 3-Phenylquinazolin-4(3H)-one compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of various inflammatory and fibrotic diseases of the respiratory tract and of the lungs as well as lung cancer, as a sole agent or in combination with other active ingredients.
  • Wnt/ -catenin signaling is a highly evolutionarily conserved pathway that plays a central role in the regulation of multiple biological developmental and adult processes such as cell fate determination, cell polarity, division, proliferation, differentiation, migration, apoptosis, tissue regeneration and homeostasis.
  • Wnt ⁇ -catenin signaling is essential for the organogenesis of various systems including heart, lungs, skin, intestines, muscles, bone, prostate, brain and kidney.
  • Wnt signaling Other non-canonical routes of Wnt signaling are considered to operate in a more ⁇ -catenin-independent manner.
  • some Wnt ligands/Fzd receptors have been shown to promote intracellular Ca 2+ release, resulting in the activation of kinases such as protein kinase C (PKC) and Ca 2+ -calmodulin- dependent protein kinase II (CamKII) (Nat Rev Immunol. 2008 Aug;8(8):581 -93).
  • PKC protein kinase C
  • Ca 2+ -calmodulin- dependent protein kinase II Ca 2+ -calmodulin- dependent protein kinase II
  • Wnt ligands can also bind to Fzd receptors independently of LRP and stimulate GTPases Rho and Rac, the latter governing ROCK and J K signaling, respectively.
  • both Wnt/Ca 2+ and PCP non-canonical pathways are closely interconnected with the canonical ⁇ -catenin-dependent Wnt pathway and could either activate or inhibit the ⁇ -catenin-driven TCF signaling depending on the biological context.
  • Complex co-switch mechanisms and signaling network cross-talks between the different Wnt pathways have been reported (Nat Rev Mol Cell Biol. 2010 Jun;l 1(6):404-13).
  • Wnt/ -catenin signaling could result due to genetic perturbations or alterations in the cellular expression, synthesis and function of different receptors, proteins and effector molecules that regulate Wnt signal transduction.
  • Dysregulated Wnt/ -catenin signaling has been implicated in the pathophysiology of numerous hereditary disorders, pathological conditions and diseases (Cellular Signalling 27 (2015) 1380-1391). That is why inhibitors of the canonical Wnt/ -catenin signaling are described for treating a wide range of acute or chronic respiratory and cardio-respiratory diseases (Respir Res. 2006 Jan 26;7: 15).
  • Lung diseases occur as a result of tissue damage to the lung (epithelium, parenchyma, vasculature), which could be caused by different genetic predispositions, infectious or non-infectious acute and chronic stimuli (including but not limited to viruses, bacteria, parasites, fungi, drugs, toxins, smoke, aerosols, allergens, mechanical injury, radiation). This leads to the stimulation of host-defense, homeostatic control and tissue repairing mechanisms and pathways.
  • Wnt/ -catenin signaling governs biological processes such as: cell-cell adhesion, inflammation, immune system regulation, stem cell maintenance, re-epithelialization, cell fate determination, cell polarity, division, proliferation, differentiation, migration, angiogenesis, apoptosis, epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast differentiation fibroblast activation, connective tissue synthesis, wound healing, fibrosis.
  • EMT epithelial-mesenchymal transition
  • fibroblast-to-myofibroblast differentiation fibroblast activation connective tissue synthesis, wound healing, fibrosis.
  • Wnt/ -catenin signaling inhibitors for the treatment of different respiratory disorders has been demonstrated in various rodent experimental animal models of lung diseases. Inhibition of Wnt/ -catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF- ⁇ and FGF-2 in vivo and in vitro (Exp Mol Pathol. 2016 Aug;101(l):22-30).
  • ICG-001 a selective inhibitor of Wnt/beta-catenin-dependent transcription
  • results in attenuation of bleomycin-induced lung fibrosis in mice preserves the epithelium, whereas late administration is able to reverse established fibrosis and significantly improves survival
  • Intratracheal treatment with ⁇ -catenin siRNA significantly reduces ⁇ -catenin expression, pulmonary fibrosis and collagen synthesis in bleomycin-administered mice compared to controls (Tohoku J Exp Med. 2011 Jan;223(l):45-54).
  • Wnt3a has been reported to activate Wnt/ -catenin signaling in lung fibroblasts, thus enhancing the expression of collagen I, vimentin and a-smooth muscle actin and other profibrotic signals (J Cell Physiol. 2014 Feb;229(2):213-24).
  • NSC668036 a small organic inhibitor of the PDZ domain in Dvl, suppressed ⁇ -catenin-driven gene transcription and abolished TGF- ⁇ -induced migration, expression of collagen I and ⁇ -smooth muscle actin (a-SMA) in fibroblasts in vitro, but also significantly suppressed lung fibrogenesis in vivo (Exp Cell Res. 2015 Feb 1 ;331(1): 115-22).
  • Targeting the Wnt/ -catenin signaling pathway by the means of a porcupine inhibitor GNF6231 also provides a therapeutic benefit to skin and lung fibrosis as it prevents progression of fibrosis and shows evidence of reversal of established fibrosis (Ann Rheum Dis.
  • Wnt/ -catenin signaling pathway is considered to also play a crucial role in pulmonary vascular remodeling (PLoS One. 2011 Apr 18;6(4):el 8883), therefore inhibition of canonical Wnt/ ⁇ -catenin signaling is an important therapeutic approach to prevent and/or reverse pulmonary vascular pathology in patients with pulmonary arterial hypertension (Drug Discov Today. 2014 Aug;19(8): 1270-6; Am J Physiol Cell Physiol. 2014 Sep l ;307(5):C415-30; J Clin Invest. 2009 Sep;119(9):2538-49).
  • Inhibition of Wnt/p-catenin signaling therefore represents an effective principle in the treatment of various inflammatory and fibrotic pulmonary and cardiovascular disorders. It is therefore an object of the present invention to provide novel compounds for the prophylaxis or treatment of abnormal Wnt/ ⁇ - catenin signaling disorders, in particular of inflammatory and fibrotic diseases of the respiratory tract and of the lungs, in humans and animals.
  • WO 2003/0334 76 describes substituted pyrimidinones as antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) for treating obesity, diabetes, depression or anxiety
  • MCHR1 melanin-concentrating hormone receptor 1
  • WO 2008/079787 describes inter alia substituted phenylquinazolin-4(3H)-ones as ADP receptor antagonists for the treatment of thrombosis
  • WO 2004/037176 describes inter alia substituted quinazolin-4(3H)-ones as factor Xa inhibitors for the treatment of thrombosis
  • WO 00/55153, EP 1163237 Bl, US 7,008,945 Bl, US 7,332,483 BB and US 7,442,704 BB describe substituted phenylquinazolin-4(3H)-ones and their use in the treatment of diseases mediated by cytokines.
  • the invention provides compounds of the formula
  • R 1 represents a hydrogen atom, methyl or a halogen atom
  • R 2 represents a phenyl group or a 5- to 10-membered heteroaryl group
  • any phenyl group and any 5- to 10-membered heteroaryl group are each optionally substituted, identically or differently, with one, two or three groups selected from a halogen atom, (Ci-C i)-alkyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)-alkylamino, hydroxy, cyano, (C1-C4)- alkoxycarbonyl, (Ci-C4)-alkoxy and trifluoromethoxy,
  • R 3 represents a hydrogen atom, methyl or a halogen atom
  • R 4 represents a group selected from a hydrogen atom, (Ci-C 4 )-alkyl and (C3-C6)-cycloalkyl,
  • (Ci-C 4 )-alkyl is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, cyclopropyl and optionally up to five fluorine atoms,
  • R 5 represents a group selected from a hydrogen atom, and (Ci-C 4 )-alkyl,
  • R 4 and R 5 together with the carbon atom they are attached form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle, where said 4- to 6-membered heterocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms,
  • (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
  • said 3- to 6-membered carbocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms
  • R 6 represents #-NR u R 12 , a 5- or 6-membered heteroaryl group, di-(Ci-C4)-alkylamino or (C1-C4)- alkoxycarbonylamino,
  • # represents the point of attachment to the carbon atom in alpha position to the carbonyl of the amide group
  • R u and R 12 represent (Ci-C 4 )-alkyl
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono- or bicyclic azaheterocycle
  • 4- to 10-membered heterocycle is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, oxo and (Ci-C4)-alkyl,
  • R 7 represents a group selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methoxymethyl, 2,2,2-trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
  • R 8 represents a hydrogen atom or fluorine
  • R 9 represents a hydrogen atom or fluorine
  • R 10 represents a hydrogen atom or fluorine
  • R 1 represents a hydrogen atom, methyl or a halogen atom
  • R 2 represents a phenyl group or a 5- to 10-membered heteroaryl group
  • any phenyl group and any 5- to 10-membered heteroaryl group are each optionally substituted, identically or differently, with one, two or three groups selected from a halogen atom, (Ci-C i)-alkyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)-alkylamino, hydroxy, cyano, (C1-C4)- alkoxycarbonyl, (Ci-C4)-alkoxy and trifluoromethoxy,
  • R 3 represents a hydrogen atom, methyl or a halogen atom
  • R 4 represents a group selected from a hydrogen atom, (Ci-C4)-alkyl and (C3-C6)-cycloalkyl,
  • (Ci-C4)-alkyl is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, cyclopropyl and optionally up to five fluorine atoms,
  • R 5 represents a group selected from a hydrogen atom, and (Ci-C4)-alkyl
  • R 4 and R 5 together with the carbon atom they are attached form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,
  • (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
  • said 3- to 6-membered carbocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms
  • R 6 represents #-NR u R 12 , a 5- or 6-membered heteroaryl group, di-(Ci-C4)-alkylamino or (C1-C4)- alkoxycarbonylamino,
  • # represents the point of attachment to the carbon atom in alpha position to the carbonyl of the amide group
  • R u and R 12 represent (Ci-C 4 )-alkyl
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono- or bicyclic azaheterocycle
  • said 4- to 10-membered heterocycle is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, oxo and (Ci-C4)-alkyl, where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
  • R 7 represents a group selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methoxymethyl, 2,2,2-trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
  • R 8 represents a hydrogen atom or fluorine
  • R 9 represents a hydrogen atom or fluorine
  • R 10 represents a hydrogen atom or fluorine
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non- hydrogen substituent on any available carbon atom or heteroatom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, 4 or 5, in particular 1 , 2 or 3.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, even more particularly fluorine or chlorine.
  • Ci-C i-alkyl and “Ci-C6-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, or 4 carbon atoms, and 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g.
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C i-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec -butyl isobutyl, or teri-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, ⁇ -propyl or isopropyl group.
  • Ci-C i-alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C4-alkyl)-0-, in which the term "Ci-C i-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, eobutoxy, isobutoxy, teri-butoxy, or an isomer thereof.
  • C3-C6-cycloalkyl and “Cs-Ce-cycloalkyl” means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl").
  • Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or a bicyclic hydrocarbon ring.
  • C3-C6-cycloalkyl and “Cs-Ce-cycloalkyl” and “3- to 6-membered carbocycle”, “3- to 7- membered carbocycle”and “4- to 6-membered carbocycle” means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms ("C3-C6-cycloalkyl”).
  • Said Cs-Ce- cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or a bicyclic hydrocarbon ring.
  • (C3-C6)-cycloalkyl and “C3-C8-cycloalkyl” mean a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C8-cycloalkyl").
  • Said C3- C8-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g.
  • bicyclo[4.2.0]octyl or octahydropentalenyl a bicyclo[4.2.0]octyl or octahydropentalenyl.
  • the term "3- to 6-membered heterocycle”, “4- to 6-membered heterocycle”, “4- to 7-membered heterocycle”, “5- to 6-membered heterocycle” and 4- to 10-membered heterocycle means a monocyclic or bicyclic, saturated heterocycle with 4 to 10, 3 to 6, 4 to 6, 4 to 7 or 5 to 6 ring atoms in total, respectively, which contains one or two ring heteroatoms from the group consisting of N, O, S, SO and SO 2 and which is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • azetidinyl oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpho- linyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-l,4-diazepinyl.
  • 3- to 6-membered azaheterocycle means a monocyclic or bicyclic, saturated heterocycle with 4 to 10, 3 to 6, 4 to 6 or 5 to 6, ring atoms in total, which contains a nitrogen atom and which may additionally contain one or two further ring heteroatoms from the group consisting of N, O, S, SO and SO2 and is attached via a ring nitrogen atom.
  • Said azaheterocycle can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 , 1 -dioxidothiolanyl, 1 ,2-oxazolidinyl,
  • oxazolidinyl or 1,3-thiazolidinyl for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3 -dioxanyl,
  • Said bicyclic heterocycloalkyl group can be azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo [3.2.1] octyl, thiazabicyclo [3.2.1] octyl, azabicyclo [3.3.1 ]nonyl, diazabicyclo [3.3.1 ]nonyl, oxazabicyclo[3.3.1]nonyl, oxazabicyclo
  • 5- to 6-membered heteroaryl means a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 6, 5 or 6 or 5 to 10 ring atoms which contains up to three identical or different ring heteroatoms from the group consisting of N, O and/or S and is attached via a ring carbon atom or optionally via a ring nitrogen atom.
  • furyl pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyri- dinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[3,4-b]pyridinyl.
  • Heteroaryl in the context of the invention preferably represents a monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • heterocycle monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • furyl pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • Mono-(Ci-C4)-alkylamino in the context of the invention means an amino group with one straight-chain or branched alkyl substituent which contains 1 , 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, for example.
  • Di-(Ci-C4)-alkylamino in the context of the invention means an amino group with two identical or different straight-chain or branched alkyl substituents which each contain 1 , 2, 3 or 4 carbon atoms, such as: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-methylamino, N-isopropyl-N-n-propylamino, NN-diisopropylamino, N-n-butyl-N-methyl- amino, and N-tert-butyl-N-methylamino, for example.
  • An oxo substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g. : tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C1-C4 as used in the present text, e.g. in the context of the definition of "Ci-C i-alkyl” or "Ci-C i-alkoxy”, means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3, or 4 carbon atoms.
  • Ci-Ce as used in the present text, e.g. in the context of the definition of "Ci-C6-alkyl”, means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C3-C6 as used in the present text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.
  • C3-C8 as used in the present text, e.g. in the context of the definition of "C3-C8-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C1-C4 encompasses Ci, C 2 , C 3 , C 4 , G-C 4 , C1-C3, C1-C2, C2-C4, C2-C3, and C 3 -C 4 ;
  • C1-C3 encompasses Ci, C 2 , C 3 , C1-C3, C1-C2, and C2-C3;
  • C2-C4 encompasses C2, C3, C 4 , C2-C4, C2-C3, and C3-C4;
  • C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , C 3 -C 6 , C3-C5, C3-C4, C 4 -C 6 , C4-C5, and C 5 -C 6 ;
  • the term "leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy (mesyl(ate), Ms), [(trifluoromethyl)sulfonyl]oxy (triflyl/(ate), Tf), [(nonafluoro- butyl)sulfonyl]oxy (nonaflate, Nf), (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromo- phenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • unnatural proportion means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.
  • isotopes examples include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium),
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)").
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or U C may be incorporated into a compound of general formula (I).
  • These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052).
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R. P.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490; A. Streitwieser et al., J. Am. Chem. Soc, 1963, 85, 2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641 ; C. L. Perrin, et al., J. Am. Chem. Soc, 2003, 125, 15008; C. L.
  • deuterium-containing compound of general formula (I) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I).
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism.
  • deuterium- containing compounds of general formula (I) having a certain pattern of one or more deuterium- hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
  • the present invention concerns a deuterium-containing compound of general formula (I) having 1, 2, 3 or 4 deuterium atoms, particularly with 1, 2 or 3 deuterium atoms.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 3H tautomer, or even a mixture in any amount of the two tautomers, namely :
  • the present invention includes all possible tautomers of the compounds of the present invention single tautomers, or as any mixture of said tautomers, in any ratio.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio.
  • polar solvents in particular water
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, terra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt, in particular as a free acid.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • the present invention covers a pharmaceutically acceptable salt of compounds of general formula (I), (I-C), supra, which is an alkali metal salt, in particular a sodium or potassium salt, or an ammonium salt derived from an organic tertiary amine, in particular choline.
  • a pharmaceutically acceptable salt of compounds of general formula (I), (I-C), supra which is an alkali metal salt, in particular a sodium or potassium salt, or an ammonium salt derived from an organic tertiary amine, in particular choline.
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester means an in vivo hydro lysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci-Ce alkoxymethyl esters, e.g. methoxymethyl, Ci-Ce alkanoyloxymethyl esters, e.g.
  • esters pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-Ci-C6 alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; l ,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-l ,3-dioxolen-2-onylmethyl ; and Ci-C6-alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, it being possible for said esters to be formed at any carboxy group in the compounds of the present invention.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethyl- propionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • R 1 represents a hydrogen atom or fluorine
  • R 2 represents a group of the formula
  • R 13 , R 18 , R 22 and R represent a hydrogen atom, a halogen atom, (Ci-C i)-alkyl, trifluoromethyl, amino, hydroxyl or cyano,
  • R 14 , R 19 , R 23 and R represent a hydrogen atom, a halogen atom, (Ci-C i)-alkyl, amino, hydroxy, cyano, (Ci-C i)-alkoxycarbonyl, (Ci-C i)-alkoxy, difluoroalkoxy or trifluoromethoxy, where said (Ci-C4)-alkyl is optionally substituted with up to three fluorine atoms,
  • R 15 , R 20 and R 2 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl, amino or hydroxy
  • R 16 , R 25 and R represents a hydrogen atom, a halogen atom, (Ci-C4)-alkyl, amino, hydroxy, cyano, (Ci-C4)-alkoxycarbonyl, (Ci-C4)-alkoxy, difluoromethoxy or trifluoromethoxy,
  • R 17 , R 21 and R 29 represents a hydrogen atom, a halogen atom, (Ci-C4)-alkyl, trifluoromethyl, amino, hydroxyl or cyano,
  • lH-pyrazol-4-yl is optionally substituted, identically or differently, with one or two groups selected from (Ci-C4)-alkyl, trifluoromethyl, difluoromethyl, amino, hydroxyl and cyano,
  • R 3 represents a hydrogen atom or fluorine
  • R 4 represents a group selected from a hydrogen atom, methyl and ethyl
  • R 5 represents a group selected from a hydrogen atom, methyl and ethyl
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring or an oxetane ring,
  • R 6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5- yl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, 2-oxa-5-azabicyclo[2.2.2]oct-5-yl, 4-methylpiperazin-l -yl, 4-ethylpiperazin-l -yl, 4-cyclopropylpiperazin-l -yl, 4-isopropylpiperazin-l -yl, 4- isobutylpiperazin-1 -yl, 6-methyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-ethyl-3,6- diazabicyclo[3.1.1 ]hept-3-yl, 6-cyclopropyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-is
  • R 7 represents a group selected from trifluoromethoxy, difluoromethoxy, methoxymethyl, 2,2,2- trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
  • R 8 represents a hydrogen atom or fluorine
  • R 9 represents a hydrogen atom or fluorine
  • R 10 represents a hydrogen atom or fluorine
  • R 1 represents a hydrogen atom or fluorine
  • R 2 represents a group of the formula
  • R 13 , R 18 , R 22 and R 26 represent a hydrogen atom, fluorine or methyl
  • R 14 , R 19 , R 23 and R 27 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 , R 20 and R 24 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
  • R 16 , R 25 and R 28 represent a hydrogen atom
  • R 17 and R 21 represent a hydrogen atom
  • R 29 represents a hydrogen atom, fluorine or methyl
  • R 3 represents a hydrogen atom or fluorine
  • R 4 represents a group selected from a hydrogen atom and methyl
  • R 5 represents a group selected from a hydrogen atom and methyl
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo-
  • R 7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
  • R 8 represents a hydrogen atom
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom
  • R 1 represents a hydrogen atom or fluorine
  • R 2 represents a group of the formula
  • R 13 and R 18 represent a hydrogen atom, fluorine or methyl
  • R 14 and R 19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 and R 20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
  • R 16 represents a hydrogen atom
  • R 17 and R 21 represent a hydrogen atom
  • R 3 represents a hydrogen atom or fluorine
  • R 4 represents a group selected from a hydrogen atom and methyl
  • R 5 represents a group selected from a hydrogen atom and methyl
  • R 6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-ox
  • R 7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
  • R 8 represents a hydrogen atom
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Particular preference is also given to compounds of the formula (I) in which
  • R 1 represents a hydrogen atom or fluorine
  • R 2 represents a group of the formula
  • R 13 and R 18 represent a hydrogen atom, fluorine or methyl
  • R 14 and R 19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 and R 20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
  • R 16 represents a hydrogen atom
  • R 17 and R 21 represent a hydrogen atom
  • R 3 represents a hydrogen atom or fluorine
  • R 4 represents a group selected from a hydrogen atom and methyl
  • R 5 represents a group selected from a hydrogen atom and methyl
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-ox
  • R 7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
  • R 8 represents a hydrogen atom
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom
  • R 1 represents a hydrogen atom
  • R 1 represents fluorine
  • R 2 represents group of the formula, where
  • R 13 and R 18 represent a hydrogen atom, fluorine or methyl
  • R 14 and R 19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 and R 20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
  • R 16 represents a hydrogen atom
  • R 17 and R 21 represent a hydrogen atom
  • R 2 represents group of the formula
  • R 13 and R 18 represent a hydrogen atom, fluorine or methyl
  • R 14 and R 19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 and R 20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
  • R 16 represents a hydrogen atom
  • R 17 and R 21 represent a hydrogen atom
  • R 2 represents group of the formula
  • R 13 represents a hydrogen atom, fluorine or methyl
  • R 14 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 represents a hydrogen atom
  • R 16 represents a hydrogen atom
  • R 17 represents a hydrogen atom
  • R 2 represents group of the formula
  • R 13 represents a hydrogen atom, fluorine or methyl
  • R 14 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
  • R 15 represents a hydrogen atom
  • R 16 represents a hydrogen atom
  • R 17 represents a hydrogen atom
  • R 2 represents group of the formula
  • R 18 represents a hydrogen atom, fluorine or methyl
  • R 19 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl
  • R 20 represents a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino
  • R 21 represent a hydrogen atom
  • R 2 represents group of the formula
  • R 18 represents a hydrogen atom, fluorine or methyl
  • R 19 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl
  • R 20 represents a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino
  • R 21 represent a hydrogen atom, with the provisio that no more than one of R 18 , R 19 and R 20 is different from hydrogen, and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 3 represents represents a hydrogen atom
  • R 3 represents represents a fluorine
  • R 4 represents a group selected from a hydrogen atom and methyl
  • R 5 represents a group selected from a hydrogen atom and methyl
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 5 represents a group selected from a hydrogen atom and methyl
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 8-oxa
  • R 6 represents morpholin-4-yl or 4-methylpiperazin- 1-yl
  • morpholin-4-yl or 4-methylpiperazin- 1-yl are optionally substituted with methyl, and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers combinations of two or more of the above mentioned embodiments under the heading "further embodiments of the first aspect of the present invention”.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
  • the present invention covers methods of preparing compounds of general formula (I) as defined supra, said methods comprising the step
  • R 1 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra and,
  • X represents chlorine, bromine, iodine or triflate
  • R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra and
  • X represents chlorine, bromine, iodine or triflate
  • X represents chlorine, bromine, iodine or triflate
  • R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined for the compound of general formula (I) as defined supra,
  • X 1 represents chlorine, bromine, iodine, mesylate, triflate or tosylate
  • R 1 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra and
  • X represents chlorine, bromine, iodine or triflate
  • X 2 represents chlorine or hydroxy
  • R 1 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra and
  • X represents chlorine, bromine, iodine or triflate
  • R 1 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra,
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra,
  • R 1 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra and X represents chlorine, bromine, iodine or triflate,
  • R 2 is as defined for the compound of general formula (I) as defined supra
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 10 are as defined for the compound of general formula (I) as defined supra,
  • the compounds of the formulae (III), (V), (VII), (IX) and (X) are commercially available, known from the literature or can be prepared analogously to processes known from the literature.
  • the compounds of the formulae (X) can be prepared from the corresponding carboxylic acids analogously to processes known from the literature.
  • the present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • Suitable inert solvents for the process steps (II) + (III) ⁇ (IV) and (II) + (X) ⁇ (VI) and (XII) + (X) ⁇ (I) aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, diisopropyl - ether, methyl tert-butyl ether, 1,2-dimethoxyethane, bis-(2-methoxyethyl) ether, tetrahydrofuran or 1,4- dioxane, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2- dichloroethane, trichloroethylene or chlorobenzene or dipolar aprotic solvents such as acetonitrile, NN- dimethylformamide (DMF), NN-dimethylacetamide (DMA), dimethyl sulfoxide (
  • Suitable bases for the process step (II) + (III) ⁇ (IV) and (II) + (X) ⁇ (VI) and (XII) + (X) ⁇ (I) are the customary inorganic or organic bases.
  • These preferably include alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, if appropriate with addition of an alkali metal iodide, for example sodium iodide or potassium iodide, alkali alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(
  • the process steps (II) + (III) ⁇ (IV) and (II) + (X) ⁇ (VI) and (XII) + (X) ⁇ (I) are generally carried out in a temperature range of from -10°C to +220°C, preferably in a range from +10°C to +150°C. However, it is also possible to carry out the reaction at reduced or at elevated pressure (for example at from 0.5 to 5 bar). It may optionally be advantageous to carry out the reaction with microwave irradiation.
  • Inert solvents for the amine coupling (IV) + (V)— » ⁇ (VI) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulphoxide, NN-dimethylformamide, NN-dimethylacetamide, NN'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP
  • Suitable bases for the process step (IV) + (V)— » ⁇ (VI) are the customary inorganic or organic bases.
  • alkali metal hydroxides for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, if appropriate with addition of an alkali metal iodide, for example sodium iodide or potassium iodide, alkali alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine,
  • Suitable catalysts for the process step (IV) + (V)— » ⁇ (VI) are alkali metal iodides, for example sodium iodide, potassium iodide, sodium bromide, potassium bromide, tetrabutylammonium iodide, tetrabutylammonium bromide and DMAP. Preference is given to using potassium iodide.
  • the amine coupling (IV) + (V)—> (VI) is generally conducted within a temperature range from -20°C to +150°C, preferably at 0°C to +100°C.
  • the conversion can be effected at standard, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, standard pressure is employed. It may optionally be advantageous to carry out the reaction with microwave irradiation.
  • Suitable inert solvents for the process steps (VI) + (VII) ⁇ (VIII) and (VIII) + (IX) ⁇ (I) and (II) + (VII) —> (XI) and (XI) + (IX)—> (XII) are aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, bis-(2- methoxyethyl) ether, tetrahydrofuran or 1,4-dioxane, or dipolar aprotic solvents such as acetonitrile, NN-dimethylformamide (DMF), NN-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), NN- dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP)
  • mixtures of the solvents mentioned optionally also in a mixture with water.
  • Suitable bases for the process step (VI) + (VII) ⁇ (VIII) and (VIII) + (IX) ⁇ (I) and (II) + (VII) ⁇ (XI) and (XI) + (IX)—> (XII) are the customary inorganic or organic bases.
  • alkali metal hydroxides for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, if appropriate with addition of an alkali metal iodide, for example sodium iodide or potassium iodide, alkali alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert- butoxide, alkali metal acetates such as sodium acetate or potassium acetate, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethyl- amine, N-methylmorpholine,
  • Suitable Palladium catalysts for the process (VI) + (VII) ⁇ (VIII) and (VIII) + (IX) ⁇ (I) and (II) + (VII) —> (XI) and (XI) + (IX)—> (XII) are, for example, palladium on activated carbon, palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenyl- phosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complex, optionally in conjunction with additional phosphane ligands, for example 1,4- Bis(diphenylphosphino)butane-
  • precatalysts such as chloro-[2-(dicyclohexylphosphine)-3,6- dimethoxy-2',4',6'-triisopropyl-l , 1 '-biphenyl] [2-(2-aminoethyl)-phenyl]palladium(II) (BrettPhos precatalyst) [cf., for example, S. L. Buchwald et al., Chem. Sci.
  • phosphane ligands such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'- triisopropyl-l,r-biphenyl (BrettPhos); preference is given to bis(dibenzylideneacetone)palladium(0) in combination with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and chloro-[2- (dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-l, -biphenyl] [2-(2-aminoethyl)phenyl]- palladium(II) (BrettPhos precatalyst) or a mixture of chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy- 2
  • the process steps (VI) + (VII) ⁇ (VIII) and (VIII) + (IX) ⁇ (I) and (II) + (VII) ⁇ (XI) and (XI) + (IX) —> (XII) are generally carried out in a temperature range of from +10°C to +220°C, preferably from +20°C to +150°C, at atmospheric pressure. However, it is also possible to carry out the reaction at reduced or at elevated pressure (for example at from 0.5 to 5 bar). It may optionally be advantageous to carry out the reaction with microwave irradiation.
  • R 1 and R 3 are as defined for the compound of general formula (I) as defined supra and,
  • X represents chlorine, bromine, iodine or triflate
  • T 3 represents tert-butyl
  • X represents chlorine, bromine, iodine or triflate
  • T 3 represents tert-butyl
  • Inert solvents for the amide coupling (XIII) + (XIV)— » ⁇ (XV) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulphoxide, NN-di
  • Suitable condensing agents for the amide formation (XIII) + (XIV) —> (XV) are, for example, carbodiimides such as NN'-diethyl-, NN'-dipropyl-, NN'-diisopropyl-, NN'-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CD I), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l,2- oxazolium 3-sulphate or 2-teri-butyl-5-methylisoxazolium
  • the condensation (XIII) + (XIV)—> (XV) is generally conducted within a temperature range from - 20°C to +100°C, preferably at 0°C to +60°C.
  • the conversion can be effected at standard, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, standard pressure is employed.
  • the carboxylic acid of the formula (XIII) can also first be converted to the corresponding carbonyl chloride and the latter can then be reacted directly or in a separate reaction with an amine of the formula (XIV) to the compounds of the invention.
  • the formation of carbonyl chlorides from carboxylic acids is effected by the methods known to those skilled in the art, for example by treatment with thionyl chloride or oxalyl chloride, in the presence of a suitable base, for example in the presence of pyridine, and optionally with addition of dimethylformamide, optionally in a suitable inert solvent.
  • Suitable inert solvents for the process step (XV)— »(XVI) for example are formic acid and tri-(Ci-C4 )- alkoxy-(Ci-C i)-alkyls. Preference is given to using formic acid.
  • the process (XV)— »(XVI) is generally carried out in a temperature range of from +60°C to +180°C, preferably from 30°C to +100°C.
  • Suitable inert solvents for the process step (XVI)— »(II) for example are water or alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, esters like ethyl acetate or butyl acetate, carboxylic acids like acetic acid, ethers such as diethyl ether, diisopropyl ether, methyl teri-butyl ether, 1,2-dimethoxyethane, bis-(2-methoxyethyl) ether, tetrahydrofuran or 1,4-dioxane, or dipolar aprotic solvents such as acetonitrile, NN-dimethylformamide (DMF), NN-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) or pyridine. It is also possible to use mixtures of the solvents mentioned, optional
  • Suitable reducing agents for the process step (XVI)— »(II) are for example Tin(II) chloride, Titanium (III) chloride, Iron(III) chloride, Titanium(TV) chloride, Tin, Iron, Zinc, Indium, Aluminum, Nickel, ; preference is given to Tin(II) chloride and Titanium (III) chloride.
  • the process (XVI)— >(U) is generally carried out in a temperature range of from -80°C to +220°C, preferably from -10°C to +100°C.
  • Further compounds according to the invention can optionally also be prepared by converting functional groups of individual substituents, in particular those listed under R 2 and R 6 , starting with the compounds of the formula (I) obtained by the above processes.
  • These conversions are carried out by customary methods known to the person skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carboxamides, and also the introduction and removal of temporary protective groups.
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Detailed procedures can also be found in the Experimental, in the section on the preparation of the starting compounds and intermediates.
  • the compounds of the invention have valuable pharmacological properties and can be used for prevention and treatment of diseases in humans and animals.
  • the compounds of the invention are potent, chemically stable inhibitors of Wnt/ -catenin signaling and are therefore suitable for treatment and/or prevention of disorders and pathological processes, especially those in which of the Wnt/ -catenin signaling is involved in the course of acute or chronic respiratory diseases and cardio-respiratory diseases and/or hyperproliferative disorders.
  • these especially include inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular inflammatory and fibrotic pulmonary disorders and cardio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • disorders in particular inflammatory and fibrotic pulmonary disorders and cardio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • Lung diseases occur as a result of tissue damage to the lung (epithelium, parenchyma, vasculature, etc.), which could be caused by different genetic predispositions, infectious or non-infectious acute and chronic stimuli (including but not limited to viruses, bacteria, parasites, fungi, drugs, toxins, smoke, aerosols, allergens, mechanical injury, radiation, etc.).
  • Wnt/ -catenin signaling which govern biological processes such as: cell-cell adhesion, inflammation, immune system regulation, stem cell maintenance, re-epithelialization, cell fate determination, cell polarity, division, proliferation, differentiation, migration, angiogenesis, apoptosis, epithelial-mesenchymal transition (EMT), fibroblast- to-myo fibroblast differentiation fibroblast activation, connective tissue synthesis, would healing, fibrosis.
  • Wnt/ -catenin signaling could result in pathogenic events such as uncontrolled inflammation, angiogenesis, cellular proliferation, abnormal cell cycling/survival signals, fibrosis (J Exp Med. 2011 Jul 4; 208(7): 1339-1350), tumor formations, eventually leading to organ(s) failure and death.
  • pathogenic events such as uncontrolled inflammation, angiogenesis, cellular proliferation, abnormal cell cycling/survival signals, fibrosis (J Exp Med. 2011 Jul 4; 208(7): 1339-1350), tumor formations, eventually leading to organ(s) failure and death.
  • Non-limiting examples of such acute and chronic lung diseases and conditions resulting from aberrant activation ofWnt/ -catenin signaling include:
  • Idiopathic Fibrotic Disorders of the Lung Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (UIP), Acute Interstitial Pneumonitis (Hamman-rich Syndrome), Familial
  • Pulmonary Fibrosis Pulmonary Fibrosis, Respiratory Bronchiolitis/Desquamative Interstitial Pneumonitis, Cryptogenic Organizing Pneumonia, Nonspecific Interstitial Pneumonia, Lymphocytic Interstitial Pneumonia, Autoimmune Pulmonary Fibrosis
  • Primary ILDs Sarcoidosis, Pulmonary Langerhans Cell Histiocytosis (Eosinophilic Granuloma), Amyloidosis, Pulmonary Vasculitis, Lymphangioleiomyomatosis (+/- Tuberous
  • ILDs Connective Tissue Disease-Related Interstitial Lung Disease
  • Scleroderma/Systemic Sclerosis ILD Polymyositis-Dermatomyositis ILD, Systemic Lupus Erythematosus ILD, Rheumatoid Arthritis ILD, Mixed Connective Tissue Disease ILD, Primary Sjogren Syndrome ILD, Ankylosing Spondylitis ILD
  • Hereditary & Other ILDs Gaucher Disease, Niemann -Pick Disease, Hermansky-Pudlak Syndrome, Neurofibromatosis, Aspiration, Exogenous Lipoid Pneumonia, Lymphangitic Carcinomatosis, Pulmonary Lymphoma
  • Occupational/Environmental ILDs Silicosis, Asbestosis, Hard-Metal / Coal Workers' Pneumoconiosis, Berylliosis, Siderosis (Arc Welder) / Stannosis (Tin), Hypersensitivity Pneumonitis, Bird Breeder's Lung & Farmer's Lung
  • BPD Bronchopulmonary dysplasia
  • the compounds and compositions provided herein can be further used for prevention or treatment of numerous diseases related to abnormalities in the Wnt signaling cascade such as but not limited to: cardiovascular and heart diseases; autoimmune diseases; hematopoietic disorders; neurological diseases; gynecological disorders; renal diseases; obesity and metabolism-related disorders; infections; eye and ear diseases; hair growth disorders and other conditions with abnormal Wnt signaling.
  • the Wnt- ⁇ - catenin signaling pathway has been implicated in the embryogenesis of the joints, muscles and bone and is one of the main pathways to maintain the musculoskeletal homeostasis in adults (Nat Med. 2013 Feb; 19(2): 179-92).
  • the compounds according to the invention are also suitable for the treatment and/or prophylaxis of diseases related to a number of musculoskeletal and bone pathological disorders including but not limited to rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, high bone mass disorders, osteogenic tumors, osteosarcomas, Ewing's sarcoma, Pyle's disease, musclular dystrophy, muscular fibrotic diseases, polymyositis (PM), dermatomyositis (DM), Duchenne muscular dystrophy (DMD) (J Clin Neurol. 2016 Jul;12(3):351-60)
  • the compounds and compositions according to the invention can be further used for prevention or treatment of prophylaxis and treatment of diseases and conditions associated with abnormal regulation of other signaling cascades that Wnt/ -catenin signaling has been shown to regulate or cross-talk with and/or in which Wnt/ -catenin signaling inhibition could be beneficial and of therapeutic potential.
  • Non- limiting examples of such signaling pathways include Notch, FGF (fibroblast growth factor), EGF (epidermal growth factor), HGF, SHH (Sonic hedgehog), Hippo pathways, transforming growth factor (TGF)- , Hedgehog (Hh), Notch, ErbB signaling and others (Breast Cancer Res. 2011 Jun 10;13(3):211).
  • the compounds and compositions provided herein can be also used to treat various hyperproliferative disorders (Nat Rev Cancer. 2013 Jan;13(l): l 1 -26). Wnt/ -catenin signaling regulates cell growth, differentiation and angiogenesis, therefore irregular activation of this pathway increases the risk of malignant transformation in many cell types, tissues and organs, but also is linked to promotion of metastasis and resistance to chemotherapy (Genes & Diseases (2016) 3, l le40).
  • the inhibitors of the Wnt/ -catenin signaling offer new therapeutic avenues to treat a large variety of hyperproliferative disorders and their complications that include but are not limited to the following: psoriasis, keloids, hyperplasias affecting the skin; solid tumors; breast tumors (incl. but not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ and lobular carcinoma in situ); lung and respiratory tract tumors (incl. but not limited to small-cell carcinoma, non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma); brain tumors (incl.
  • tumors of the male and fermale reproductive organs incl. but not limited to benign prostate hyperplasia, prostate cancer, testicular cancer, endometrial, cervical, ovarian, vaginal, and vulvar cancer, uterine sarcomas
  • tumors of the digestive tract incl.
  • tumors of the urinary tract incl. but not limited to urothelial cell carcinoma, bladder, penile, kidney, renal pelvis, ureter, urethral and papillary renal cancers
  • tumors of the eye incl. but not limited to intraocular melanoma, retinoblastoma
  • liver cancers incl.
  • hepatocellular carcinoma but not limited to hepatocellular carcinoma, cholangiocarcinoma, intrahepatic bile duct carcinoma, mixed hepatocellular cholangiocarcinoma
  • skin cancers incl. but not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer
  • head and neck cancers incl. but not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer, thyroid, parathyroid and their distant metastases
  • Lymphomas incl.
  • AIDS-related lymphoma non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system
  • sarcomas incl. but not limited to soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma
  • leukaemias incl. but not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia
  • prevention or “prophylaxis” are used synonymously and refer to the prevention or reduction of the risk to develop, experience or suffer from such conditions and/or their associated symptoms.
  • treatment includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states.
  • therapy is understood here to be synonymous with the term “treatment”.
  • prevention means prevention, prophylaxis and “preclusion” are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.
  • the treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
  • the present invention thus further provides for the use of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further provides for the use of the compounds according to the invention for production of a medicament for treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further provides a medicament comprising at least one of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further provides for the use of the compounds according to the invention in a method for treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further provides a method of treatment and/or prevention of disorders, especially of the aforementioned disorders, using an effective amount of at least one of the compounds according to the invention.
  • the compounds of general formula (I), as described supra, or stereoisomers, tautomers, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same are suitable for the treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the present invention thus further provides for the use of the compounds according to the invention for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the present invention further provides for the use of the compounds according to the invention for production of a medicament for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the present invention further provides a medicament comprising at least one of the compounds according to the invention for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the present invention further provides for the use of the compounds according to the invention in a method for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the present invention further provides a method of treatment and/or prevention of disorders, especially of inflammatory and fibrotic pulmonary disorders and cardiopulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer, using an effective amount of at least one of the compounds according to the invention.
  • disorders especially of inflammatory and fibrotic pulmonary disorders and cardiopulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the compounds according to the invention can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • the compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )),
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ® ), sorbitan fatty acid esters (such as, for example, Span ® ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween ® ), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor ® ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic ® ),
  • buffers for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ® ); alginates, gelatine),
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol ® )
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol ® )
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ® )
  • mould release agents for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ® )
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ® )), • capsule materials (for example gelatine, hydroxypropylmethylcellulose),
  • polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • antioxidants for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • An embodiment of the invention are pharmaceutical compositions comprising at least one compound of formula (I) according to the invention, preferably together with at least one inert, non-toxic, pharmaceutically suitable auxiliary, and the use of these pharmaceutical compositions for the above cited purposes.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and car dio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • inflammatory and fibrotic pulmonary disorders and car dio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non- fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the invention also relates to pharmaceutical compositions containing at least one of the compounds according to the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the abovementioned diseases.
  • Suitable combinations could be for example but not limited to:
  • Serine / threonine / tyrosine kinase inhibitors such as but not limited to, preferably Nintedanib, Regorafenib, Imatinib, Gefitinib, Erloinib, Sorafenib, Dasatinib, Sunitinib, Nilotinib, Lapatinib, Pazotinib, Ruxolitinib, Crizotinib, Vemurafenib, Vandetanib, Ponatinib, Cabozantinib, Tofacitinib, Bosutinib, Axitinib, Ibrutinib, Afatinib, Dabrafenib, Trametinib, Idelalisib, Ceritinib, Lentavatinib, Palbocicnib;
  • Antifibrotic agents such as but not limited to, preferably Pirfenidone, adenosine A2b receptor antagonists, sphingosine 1 -phosphate receptor 3 (S1P3) antagonists, autotaxin inhibitors, lysophosphatidic acid receptors 1 (LPA- 1) and lysophosphatidic acid receptor 2 (LPA-2) antagonists, FP receptor antagonists, lysylxidase (LOX) inhibitors, lysyl oxidase-like-2 inhibitors, CTGF inhibitors, IL-13 antagonists, TGF- ⁇ antagonists, av integrin antagonists, CCR2 antagonists;
  • Pirfenidone adenosine A2b receptor antagonists
  • S1P3 sphingosine 1 -phosphate receptor 3
  • autotaxin inhibitors lysophosphatidic acid receptors 1 (LPA- 1) and lysophosphatidic acid receptor 2 (LPA-2) antagonists
  • FP receptor antagonists
  • the compounds according to the invention are administered in combination with supplement oxygen therapy
  • Anti-obstructive or anti-inflammatory agents for the treatment of chronic obstructive pulmonary disease COPD
  • COPD chronic obstructive pulmonary disease
  • corticosteroids for example fluticasone, budesonide, prednisolone
  • methylxanthines for example theophylline
  • long-acting bronchodilators long-acting ⁇ 2 agonists, muscarinic antagonists
  • combination drugs for example glycopyrrolate/formoterol, glycopyrrolate/indacaterol, tiotropium/olodaterol, umeclidinium
  • combination drugs for example glycopyrrolate/formoterol, glycopyrrolate/indacaterol, tiotropium/olodaterol, ume
  • Prostacyclin analogs-based vasodilators for example epoprostenol, beraprost, iloprost, treprostinil, selexipag;
  • Endothelin receptor antagonists for example bosentan, darusentan, macitentan, sitaxsentan and ambrisentan;
  • Organic nitrates and NO donors such as, for example, sodium nitroprusside, nitroglycerol, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phospho diesterases
  • Sildenafil, vardenafil, tadalafil, ureafil, dasantafil, avanafil, mirodenafil or lodenafil inhibitors of the phospho diesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE5 inhibitors, for example Sildenafil, vardenafil, tadalafil, ureafil, dasantafil, avanafil, mirodenafil or lodenafil;
  • sGC Soluble guanylate cyclase
  • the compounds according to the invention are administered in combination with a calcium channel blockers, for example amlodipine, diltiazem, verapamil, nifedipine;
  • a calcium channel blockers for example amlodipine, diltiazem, verapamil, nifedipine;
  • Blood pressure-lowering active substances for example and preferably from the group of angiotensin All antagonists, for example losaran, candesartan, valsartan, telmisartan, emburdenan, irbesartan, olmesartan, eprosartan or azilartartan or a dual angiotensin All antagonists / NEP inhibitor, such as and preferably LCZ696 valsartan/sacubitrile, ACE inhibitors, for example enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, for example aliskiren, SPP-600 or SPP-800, ⁇ - blockers, for example propranolol, atenolol, timolol, pin
  • Antiarrhythmic agents that interfere with the sodium (Na+) channel anti-sympathetic nervous system agents, agents that affect potassium (K+) efflux, agents affect calcium channels and the AV node, agents that work by other mechanisms;
  • Anticoagulants, antiplatelets, fibrinolytic agents and low molecular weight (LMW)-heparin derivatives for example vitamin K antagonists, for example coumarins and non-coumarin 1,3-indandione derivatives; heparin (UFH) and low-molecular-weight heparins (LMW), for example tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (Ml 18) and EP-42675/ORG42675; direct thrombin inhibitors (DTI) such as, for example, Pradaxa (dabigatran), atecegatran (AZD-0837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanogitran (BIBT-986 and prodrug BIBT
  • Anti-inflammatory, immunomodulating, immunosuppressive and / or cytotoxic agents for example systemic or inhaled corticosteroids, non-steroidal anti-inflammatory drugs, as well as acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, steroids, azithromycin, pirfenidone or etanercept;
  • Synthetic and biological disease-modifying antirheumatic drugs - e.g. abatacept, adalimumab, azathioprine, chloroquine and hydroxychloroquine, ciclosporin (Cyclosporin A), D- penicillamine, etanercept, golimumab, gold salts, infliximab, leflunomide, methotrexate, minocycline, rituximab, sulfasalazine (SSZ); Antagonists of growth factors, cytokines and chemokines, exemplarily and preferentially antagonists of TGF- ⁇ , CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17, IL-33 and integrins;
  • Chemotherapeutic agents such as, e.g. for the therapy of neoformations (neoplasia) of the lungs or other organs;
  • HNE human neutrophil elastase
  • PREP prolyl endopetidase
  • MMPs matrix metalloproteinases
  • MMP-1, MMP-3, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11, and MMP-13 matrix metalloproteinases
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as, for example, and preferably ezetimibe, tiqueside or pamaqueside;
  • a cholesterol absorption inhibitor such as, for example, and preferably ezetimibe, tiqueside or pamaqueside;
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example, and preferably orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, for example, and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide;
  • a polymeric bile acid adsorber such as, for example, and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide;
  • the compounds according to the invention are administered in combination with a CETP-Inhibitor (Torcetrapib, JJT-705 or CETP-vaccine), thyroid receptor agonists (D-Thyroxin, 3,5,3'-Triiodothyronin (T3), CGS 23425 or Axitirome), squalene synthase inhibitors, AC AT inhibitoren, MTP inhibitors, PPAR- ⁇ -, PPAR- ⁇ - and/or PPAR-8-agonists, cholesterol absorption inhibitors, polymeric bovine acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists;
  • a CETP-Inhibitor Teorcetrapib, JJT-705 or CETP-vaccine
  • thyroid receptor agonists D-Thyroxin, 3,5,3'-Triiodothyronin (T3), CGS 23425 or Axitirome
  • the compounds according to the invention are administered in combination with compounds which block the binding of serotonin to its receptor, examples and preferably antagonists of the 5-HT2B receptor;
  • Rho kinase inhibitory compounds such as, for example, and preferably Fasudil, Y 27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
  • the compounds according to the invention are administered in combination with proton pump inhibitors (PPIs) such as omeprazole, aspirin and omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole, esomeprazole magnesium/naproxen, omeprazole/sodium bicarbonate.
  • PPIs proton pump inhibitors
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with known agents of the same indication treatment group, such as agents used for the treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
  • the inventive compounds are administered in combination with one or more further agents selected from the group of serine / threonine / tyrosine kinase inhibitors and/or antifibrotic agents.
  • the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day, and more preferably from about 0.01 mg/kg to about 10 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the average daily oral dosage regimen will preferably be from 0.01 to 30 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of formula (I) according to the invention are administered orally once or twice or three times a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once or twice a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once a day. For the oral administration, a rapid release or a modified release dosage form may be used.
  • PYBOP benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate quant. Quantitative RP reversed phase (in HPLC)
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • 'H-NMR data of selected compounds are listed in the form of 'H-NMR peaklists.
  • ⁇ value in ppm is given, followed by the signal intensity, reported in round brackets.
  • the ⁇ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: ⁇ (intensityi), 82 (intensity2), ... , ⁇ ; (intensity), ... , ⁇ ⁇ (intensity ⁇ .
  • the intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown.
  • a 'H-NMR peaklist is similar to a classical 'H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation.
  • peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compounds by known methods can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 'H-NMR interpretation.
  • Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit.
  • the reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • Method 1 Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 mm x 1 mm; mobile phase A: 1 1 of water + 0.25 ml of 99% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A ⁇ 1.2 min 5% A ⁇ 2.0 min 5% A; oven: 50°C; flow rate: 0.40 ml/min; UV detection: 208-400 nm.
  • Method 2 Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 mm x 1 mm; mobile phase A: 1 1 of water + 0.25 ml of 99% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 95% A ⁇ 6.0 min 5% A ⁇ 7.5 min 5% A; oven: 50°C; flow rate: 0.35 ml/min; UV detection: 210-400 nm.
  • Method 3 MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; column: Agient ZORBAX Extend-C18 3.0 mm x 50 mm 3.5 micron; mobile phase A: 1 1 of water + 0.01 mol of ammonium carbonate, mobile phase B: 1 1 of acetonitrile; gradient: 0.0 min 98% A ⁇ 0.2 min 98% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; oven: 40°C; flow rate: 1.75 ml/min; UV detection: 210 nm.
  • Method 4 Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 mm x 2.1 mm; mobile phase A: 1 1 of water + 0.25 ml of 99% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A ⁇ 0.3 min 90% A ⁇ 1.7 min 5% A ⁇ 3.0 min 5% A; oven: 50°C; flow rate: 1.20 ml/min; UV detection: 205-305 nm.
  • Method 5 Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m x 200 ⁇ x 0.33 ⁇ ; constant helium flow rate: 1.20 ml/min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C/min ⁇ 300°C (maintained for 3.33 min).
  • Method 6 MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1 mm x 75 mm, C18 1.8 ⁇ ; mobile phase A: 1 1 of water + 0.01%) formic acid; mobile phase B: 1 1 of acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B ⁇ 2.5 min 95% B ⁇ 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210 nm/ Optimum Integration Path 210-300 nm.
  • Method 7 Instrument: Waters Single Quad MS System; Instrument Waters UPLC Acquity; Column : Waters BEH CI 8 1.7 ⁇ 50 x 2.1 mm; Eluent A: 1 1 water + 1.0 mL (25% ammonia)/L, Eluent B: 1 1 acetonitrile; Gradient: 0.0 min 92% A ⁇ 0.1 min 92% A ⁇ 1.8 min 5% A ⁇ 3.5 min 5% A; Oven: 50°C; Flow: 0.45 niL/min; UV-Detection: 210 nm (208-400 nm)
  • Method 8 Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m x 200 ⁇ x 0.33 ⁇ ; constant helium flow rate: 1.20 ml/min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C/min ⁇ 300°C (maintained for 3.33 min).
  • Method 9 Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25- 2 MM; eluent A: water + 0.0375 vol %> trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol %> trifluoroacetic acid; gradient: 0-0.8 min, 5-95%> B, 0.8-1.2 min 95%> B; flow 1.5 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.
  • Method 10 Instrument: Hewlett Packard HP 1100 Series CS Multikrom 100-3 system; column: 60 mm x 4.6 mm, CI 8 5 ⁇ ; mobile phase A: acetonitrile + 1 % formic acid; mobile phase B: water + 1 % formic acid; gradient: 0.0 min 20% A ⁇ 8.0 min 80% A ⁇ 10.0 min 90% A; oven: 35°C; flow rate: 1. 0 ml/min; UV detection: 254 nm.
  • Method 11 Instrument: SHIMADZU LCMS-2020; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B, 1.2-1.21 min 5% B, 1.21 -1.55 min 5% B; flow 1.5 ml/min; temperature: 50 °C; UV detection: 220 nm & 254 nm.
  • Method 12 Instrument: SHIMADZU LCMS-2020; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 0-60% B, 0.8-1.2 min 60% B, 1.2-1.21 min 0% B, 1.21 -1.55 min 0%) B; flow 1.5 ml/min; temperature: 50 °C; UV detection: 220 nm & 254 nm.
  • Microwave reactor used was a "single-mode" instrument of the EmrysTM Optimizer type.
  • the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality.
  • a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.
  • any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process.
  • names and structural formulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt” should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.
  • tert-butyl (5-bromo-2- ⁇ [3-nitro-4-(trifluoromethoxy)phenyl]carbamoyl ⁇ phenyl)carbamate (72.6 g, 140 mmol) was dissolved in formic acid (220 ml, 5.8 mol) and this mixture was refluxed for 3 hours. The reaction mixture was then poured over water and the pH was adjusted to pH 8 with 33% aqueous solution of sodium hydroxide. The suspension was filtered, the solid was washed with water and dried under vacuum to provide 58.7 g (95 % purity, 93 % yield) of the product.
  • l-(morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (CAS 1257236-65-9) (858 mg, 4.13 mmol) was suspended in dichloromethane (46 ml) and l -chloro-N,N,2-trimethylprop-l -en- 1 -amine (760 ⁇ , 96 % purity, 5.5 mmol) was added. This mixture was stirred at rt for 16 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (46 ml) and the mixture was once more evaporated.
  • reaction mixture was then partitioned between 6 mL of water and 20 mL of ethyl acetate and extractive work -up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate 100:0 to 50:50 to provide 95.0 mg (34 % yield) of the title product.
  • reaction mixture was then partitioned between 6 mL of water and 25 mL of ethyl acetate and extractive work-up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 100:0 to 50:50 to provide finally the title product. 63.0 mg (23 % yield).
  • the reaction mixture was then evaporated at 40°C and the residue was partitioned between 30 mL of water and 150 mL of ethyl acetate. Extractive work-up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was stirred with MTBE for 1 h, filtered and dried. The solid was then purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 100:0 to 93:7 to provide 1.40 g (50 % yield) of the title product.
  • the cooled mixture was diluted with 100 ml ethyl acetate and the aqueous phase was extracted twice with 50 ml ethyl acetate.
  • the combined organic solvents were washed with a saturated aqueous NaHC03 solution, and brine, dried over sodium sulfate, and the solvent removed in vacuo.
  • the residue was triturated with little DCM, the solid filtered, washed with ether, and dried.
  • the product was obtained as off-white solid (7.0 g, 68 % yield, 92 % purity) and used as such in the next step without further purification.
  • the aqueous phase was extracted with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate, and the solvent removed in vacuo.
  • the crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 3: 1) and it was obtained as yellow solid (3.10 g, 58 % yield, 97 % purity).
  • the cooled mixture was diluted with ethyl acetate (100 ml) and the aqueous phase was extracted with ethyl acetate (2 x 50 ml).
  • the combined organic solvents were washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and the solvent was removed in vacuo.
  • the residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate 4: 1) to deliver 2.50 g (92 % purity, 27 % yield) of the title compound.
  • the aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed in vacuo.
  • the crude product was purified by column chromatography on silica gel (Cyclohexane/ethyl acetate 3: 1) to deliver 2.20 g (52 % yield) of the title compound.

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Abstract

The present invention covers substituted 3-Phenylquinazolin-4(3H)-one compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of various inflammatory and fibrotic diseases of the respiratory tract and of the lungs as well as lung cancer, as a sole agent or in combination with other active ingredients.

Description

SUBSTITUTED 3-PHENYLOUINAZOLIN-4(3H)-ONES AND USES THEREOF
The present invention covers substituted 3-Phenylquinazolin-4(3H)-one compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of various inflammatory and fibrotic diseases of the respiratory tract and of the lungs as well as lung cancer, as a sole agent or in combination with other active ingredients.
BACKGROUND The Wnt/ -catenin signaling is a highly evolutionarily conserved pathway that plays a central role in the regulation of multiple biological developmental and adult processes such as cell fate determination, cell polarity, division, proliferation, differentiation, migration, apoptosis, tissue regeneration and homeostasis. Wnt^-catenin signaling is essential for the organogenesis of various systems including heart, lungs, skin, intestines, muscles, bone, prostate, brain and kidney.
There are at least three known routes for Wnt signal transduction to date: 1. Canonical β-catenin dependent pathway 2. Ca2+-dependent non-canonical pathway 3. Planar cell polarity (PCP) non- canonical pathway.
The current understanding of the canonical β-catenin dependent Wnt signaling involves numerous Wnt secreted glycoproteins/ligands, which first bind to different Frizzled (Fzd) receptors and the co -receptor low density lipoprotein receptor-related proteins (LRP), and thereby activate the entire downstream cascade (Nat Rev Mol Cell Biol. 2009 Jul;10(7):468-77). The recruitment of scaffolding protein Dishevelled (Dvl) promotes the phosphorylation of the LRP receptors, activates and engages the Axin complex to the receptors at the plasma membrane. This process is considered to lead to inhibition of the Axin-mediated β-catenin phosphorylation, the latter considered key for the stabilization of β-catenin (Cell. 2006 Nov 3;127(3):469-80). Despite the large variety of effector molecules, ligands, receptors and transduction routes involved, the hallmark of the canonical pathway includes the accumulation of protein β-catenin in the cytoplasm and its subsequent translocation into the nucleus. Overall, this process results in formation of complexes with T-cell factor/lymphoid enhancer factor (TCF/LEF) or several other co-factors such as p300 and CREB binding protein (CBP), hence trigger the transcription of Wnt target genes.
Other non-canonical routes of Wnt signaling are considered to operate in a more β-catenin-independent manner. For instance, some Wnt ligands/Fzd receptors have been shown to promote intracellular Ca2+ release, resulting in the activation of kinases such as protein kinase C (PKC) and Ca2+-calmodulin- dependent protein kinase II (CamKII) (Nat Rev Immunol. 2008 Aug;8(8):581 -93). The net effect involves the activation of a phosphatase named calcineurin, subsequently triggering the dephosphorylation and nuclear accumulation of the transcription factor NF-AT. In addition, Wnt ligands can also bind to Fzd receptors independently of LRP and stimulate GTPases Rho and Rac, the latter governing ROCK and J K signaling, respectively. Of note, both Wnt/Ca2+ and PCP non-canonical pathways are closely interconnected with the canonical β-catenin-dependent Wnt pathway and could either activate or inhibit the β-catenin-driven TCF signaling depending on the biological context. Complex co-switch mechanisms and signaling network cross-talks between the different Wnt pathways have been reported (Nat Rev Mol Cell Biol. 2010 Jun;l 1(6):404-13).
Abnormal Wnt/ -catenin signaling could result due to genetic perturbations or alterations in the cellular expression, synthesis and function of different receptors, proteins and effector molecules that regulate Wnt signal transduction. Dysregulated Wnt/ -catenin signaling has been implicated in the pathophysiology of numerous hereditary disorders, pathological conditions and diseases (Cellular Signalling 27 (2015) 1380-1391). That is why inhibitors of the canonical Wnt/ -catenin signaling are described for treating a wide range of acute or chronic respiratory and cardio-respiratory diseases (Respir Res. 2006 Jan 26;7: 15).
Lung diseases occur as a result of tissue damage to the lung (epithelium, parenchyma, vasculature), which could be caused by different genetic predispositions, infectious or non-infectious acute and chronic stimuli (including but not limited to viruses, bacteria, parasites, fungi, drugs, toxins, smoke, aerosols, allergens, mechanical injury, radiation). This leads to the stimulation of host-defense, homeostatic control and tissue repairing mechanisms and pathways. Wnt/ -catenin signaling as one of them, governs biological processes such as: cell-cell adhesion, inflammation, immune system regulation, stem cell maintenance, re-epithelialization, cell fate determination, cell polarity, division, proliferation, differentiation, migration, angiogenesis, apoptosis, epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast differentiation fibroblast activation, connective tissue synthesis, wound healing, fibrosis. (Am J Respir Cell Mol Biol. 2010 Jan;42(l):21 -31). If the homeostatic balance in the injured tissue is not successfully restored, the dysregulation and aberrant activation of Wnt/β- catenin signaling (Nat Med. 2016 Feb; 22(2): 154-162) results in pathogenic events such as uncontrolled inflammation, angiogenesis, cellular proliferation, abnormal cell cycling/survival signals, fibrosis (J Exp Med. 2011 Jul 4; 208(7): 1339-1350), tumor formations, eventually leading to organ(s) failure and death.
The possibility of using Wnt/ -catenin signaling inhibitors for the treatment of different respiratory disorders has been demonstrated in various rodent experimental animal models of lung diseases. Inhibition of Wnt/ -catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-βΙ and FGF-2 in vivo and in vitro (Exp Mol Pathol. 2016 Aug;101(l):22-30). Administration of ICG-001, a selective inhibitor of Wnt/beta-catenin-dependent transcription, results in attenuation of bleomycin-induced lung fibrosis in mice, preserves the epithelium, whereas late administration is able to reverse established fibrosis and significantly improves survival (Proc Natl Acad Sci U S A. 2010 Aug 10;107(32): 14309-14). Intratracheal treatment with β-catenin siRNA significantly reduces β-catenin expression, pulmonary fibrosis and collagen synthesis in bleomycin-administered mice compared to controls (Tohoku J Exp Med. 2011 Jan;223(l):45-54). Furthermore, Wnt3a has been reported to activate Wnt/ -catenin signaling in lung fibroblasts, thus enhancing the expression of collagen I, vimentin and a-smooth muscle actin and other profibrotic signals (J Cell Physiol. 2014 Feb;229(2):213-24). Inhibition of Wnt/ -catenin signaling by XAV939, a small molecule that specifically inhibits Tankyrase 1/2, promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury (Am J Physiol Cell Physiol. 2014 Aug l ;307(3):C234-44). NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-βΙ -induced migration, expression of collagen I and α-smooth muscle actin (a-SMA) in fibroblasts in vitro, but also significantly suppressed lung fibrogenesis in vivo (Exp Cell Res. 2015 Feb 1 ;331(1): 115-22). Targeting the Wnt/ -catenin signaling pathway by the means of a porcupine inhibitor GNF6231 also provides a therapeutic benefit to skin and lung fibrosis as it prevents progression of fibrosis and shows evidence of reversal of established fibrosis (Ann Rheum Dis. 2016 Apr;76(4):773-778). Because fibrotic lungs exhibit aberrant activation of Wnt/ -catenin signaling (Am J Pathol. 2003 May;162(5): 1495-502), targeting this pathway is considered to be an effective therapeutic approach. In addition, a pathway- based association study showed variants from Wnt signaling genes contributing to asthma susceptibility (Clin Exp Allergy. 2017 May;47(5):618-626), whereas blockade of Wnt/ -catenin signaling leads to the attenuation of different experimental asthma models in mice (Allergy. 2017 Apr;72(4):579-589; J Asthma. 2017 May;54(4):335-340). Wnt/ -catenin signaling pathway is considered to also play a crucial role in pulmonary vascular remodeling (PLoS One. 2011 Apr 18;6(4):el 8883), therefore inhibition of canonical Wnt/ β-catenin signaling is an important therapeutic approach to prevent and/or reverse pulmonary vascular pathology in patients with pulmonary arterial hypertension (Drug Discov Today. 2014 Aug;19(8): 1270-6; Am J Physiol Cell Physiol. 2014 Sep l ;307(5):C415-30; J Clin Invest. 2009 Sep;119(9):2538-49).
Inhibition of Wnt/p-catenin signaling therefore represents an effective principle in the treatment of various inflammatory and fibrotic pulmonary and cardiovascular disorders. It is therefore an object of the present invention to provide novel compounds for the prophylaxis or treatment of abnormal Wnt/β- catenin signaling disorders, in particular of inflammatory and fibrotic diseases of the respiratory tract and of the lungs, in humans and animals.
WO 2003/0334 76 describes substituted pyrimidinones as antagonists of the melanin-concentrating hormone receptor 1 (MCHR1) for treating obesity, diabetes, depression or anxiety, and WO 2008/079787 describes inter alia substituted phenylquinazolin-4(3H)-ones as ADP receptor antagonists for the treatment of thrombosis, WO 2004/037176 describes inter alia substituted quinazolin-4(3H)-ones as factor Xa inhibitors for the treatment of thrombosis, and WO 00/55153, EP 1163237 Bl, US 7,008,945 Bl, US 7,332,483 BB and US 7,442,704 BB describe substituted phenylquinazolin-4(3H)-ones and their use in the treatment of diseases mediated by cytokines.
DESCRIPTION of the INVENTION
The invention provides compounds of the formula
Figure imgf000005_0001
in which
R1 represents a hydrogen atom, methyl or a halogen atom,
R2 represents a phenyl group or a 5- to 10-membered heteroaryl group,
where any phenyl group and any 5- to 10-membered heteroaryl group are each optionally substituted, identically or differently, with one, two or three groups selected from a halogen atom, (Ci-C i)-alkyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)-alkylamino, hydroxy, cyano, (C1-C4)- alkoxycarbonyl, (Ci-C4)-alkoxy and trifluoromethoxy,
where said (Ci-C4)-alkyl is optionally substituted with hydroxy or up to five fluorine atoms,
R3 represents a hydrogen atom, methyl or a halogen atom,
R4 represents a group selected from a hydrogen atom, (Ci-C4)-alkyl and (C3-C6)-cycloalkyl,
where said (Ci-C4)-alkyl is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, cyclopropyl and optionally up to five fluorine atoms,
R5 represents a group selected from a hydrogen atom, and (Ci-C4)-alkyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or
R4 and R5 together with the carbon atom they are attached form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle, where said 4- to 6-membered heterocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms where said 3- to 6-membered carbocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
R6 represents #-NRuR12, a 5- or 6-membered heteroaryl group, di-(Ci-C4)-alkylamino or (C1-C4)- alkoxycarbonylamino,
where
# represents the point of attachment to the carbon atom in alpha position to the carbonyl of the amide group,
Ru and R12 represent (Ci-C4)-alkyl,
where said (Ci-C4)-alkyl is optionally substituted with (Ci-C4)-alkoxy, or
R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono- or bicyclic azaheterocycle
where said 4- to 10-membered heterocycle is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, oxo and (Ci-C4)-alkyl,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
R7 represents a group selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methoxymethyl, 2,2,2-trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
R8 represents a hydrogen atom or fluorine,
R9 represents a hydrogen atom or fluorine,
R10 represents a hydrogen atom or fluorine,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
Preference is given to compounds of the formula (I) in which
R1 represents a hydrogen atom, methyl or a halogen atom,
R2 represents a phenyl group or a 5- to 10-membered heteroaryl group,
where any phenyl group and any 5- to 10-membered heteroaryl group are each optionally substituted, identically or differently, with one, two or three groups selected from a halogen atom, (Ci-C i)-alkyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)-alkylamino, hydroxy, cyano, (C1-C4)- alkoxycarbonyl, (Ci-C4)-alkoxy and trifluoromethoxy,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms,
R3 represents a hydrogen atom, methyl or a halogen atom,
R4 represents a group selected from a hydrogen atom, (Ci-C4)-alkyl and (C3-C6)-cycloalkyl,
where said (Ci-C4)-alkyl is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, cyclopropyl and optionally up to five fluorine atoms,
R5 represents a group selected from a hydrogen atom, and (Ci-C4)-alkyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or
R4 and R5 together with the carbon atom they are attached form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,
where said 4- to 6-membered heterocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms where said 3- to 6-membered carbocycle is optionally substituted with one or two (Ci-C4)-alkyl groups and optionally up to four fluorine atoms,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
R6 represents #-NRuR12, a 5- or 6-membered heteroaryl group, di-(Ci-C4)-alkylamino or (C1-C4)- alkoxycarbonylamino,
where
# represents the point of attachment to the carbon atom in alpha position to the carbonyl of the amide group,
Ru and R12 represent (Ci-C4)-alkyl,
where said (Ci-C4)-alkyl is optionally substituted with (Ci-C4)-alkoxy, or
R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono- or bicyclic azaheterocycle
where said 4- to 10-membered heterocycle is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, oxo and (Ci-C4)-alkyl, where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
R7 represents a group selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methoxymethyl, 2,2,2-trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
R8 represents a hydrogen atom or fluorine,
R9 represents a hydrogen atom or fluorine,
R10 represents a hydrogen atom or fluorine,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non- hydrogen substituent on any available carbon atom or heteroatom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, 4 or 5, in particular 1 , 2 or 3.
As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means "1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".
When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents.
As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
The term "ring substituent" means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
The term "comprising" when used in the specification includes "consisting of.
If within the present text any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere in the present text.
The terms as mentioned in the present text have the following meanings: The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, even more particularly fluorine or chlorine.
The term "Ci-C i-alkyl" and "Ci-C6-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, or 4 carbon atoms, and 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 1 , 1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1 ,2-dimethylbutyl or 1 ,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C i-alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec -butyl isobutyl, or teri-butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, ^-propyl or isopropyl group..
The term "Ci-C i-alkoxy" means a linear or branched, saturated, monovalent group of formula (Ci-C4-alkyl)-0-, in which the term "Ci-C i-alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, eobutoxy, isobutoxy, teri-butoxy, or an isomer thereof.
The term "C3-C6-cycloalkyl" and "Cs-Ce-cycloalkyl" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl"). Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or a bicyclic hydrocarbon ring. The term "3- to 6-membered cycloalkyl" is equivalent to a "C3-C6-cycloalkyl", Thus a "4-membered cycloalkyl group" has the same meaning as a "C4- cycloalkyl group".
The term "C3-C6-cycloalkyl" and "Cs-Ce-cycloalkyl" and "3- to 6-membered carbocycle", "3- to 7- membered carbocycle"and "4- to 6-membered carbocycle" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms ("C3-C6-cycloalkyl"). Said Cs-Ce- cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or a bicyclic hydrocarbon ring. The term "3- to 6-membered carbocycle" is equivalent to a "C3-C6-cycloalkyl", thus a "4-membered carbocycle" has the same meaning as a "C i-cycloalkyl group".
The terms "(C3-C6)-cycloalkyl" and "C3-C8-cycloalkyl" mean a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C8-cycloalkyl"). Said C3- C8-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl. The term "3- to 6-membered heterocycle", "4- to 6-membered heterocycle", "4- to 7-membered heterocycle", "5- to 6-membered heterocycle" and 4- to 10-membered heterocycle means a monocyclic or bicyclic, saturated heterocycle with 4 to 10, 3 to 6, 4 to 6, 4 to 7 or 5 to 6 ring atoms in total, respectively, which contains one or two ring heteroatoms from the group consisting of N, O, S, SO and SO2 and which is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom. The following may be mentioned by way of example: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpho- linyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-l,4-diazepinyl. Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.
The term "3- to 6-membered azaheterocycle", "4- to 6-membered azaheterocycle", "5- to 6-membered azaheterocycle" and 4- to 10-membered azaheterocycle means a monocyclic or bicyclic, saturated heterocycle with 4 to 10, 3 to 6, 4 to 6 or 5 to 6, ring atoms in total, which contains a nitrogen atom and which may additionally contain one or two further ring heteroatoms from the group consisting of N, O, S, SO and SO2 and is attached via a ring nitrogen atom.
Said azaheterocycle, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 , 1 -dioxidothiolanyl, 1 ,2-oxazolidinyl,
1.3- oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3 -dioxanyl,
1.4- dioxanyl or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, 1 ,4-oxazepan-4-yl, 1,4-diazepan-l -yl, for example. Said bicyclic heterocycloalkyl group, without being limited thereto, can be azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo [3.2.1] octyl, thiazabicyclo [3.2.1] octyl, azabicyclo [3.3.1 ]nonyl, diazabicyclo [3.3.1 ]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo [3.3. l]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo [3.3.2] decyl, thiazabicyclo[3.3.2]decyl,azabicyclo[4.2.2]decyl, 6-oxa-3- azabicyclo [3. l .l]hept-3-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 2- oxa-5-azabicyclo[2.2.2]oct-5-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, 2,5- diazabicyclo[2.2.2]oct-2-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl, 3,7-diazabicyclo[3.3.1]non-3-yl,
The term "5- to 6-membered heteroaryl", "5- or 6-membered heteroaryl" and "5- to 10-membered heteroaryl" means a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 6, 5 or 6 or 5 to 10 ring atoms which contains up to three identical or different ring heteroatoms from the group consisting of N, O and/or S and is attached via a ring carbon atom or optionally via a ring nitrogen atom. The following may be mentioned by way of example: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyri- dinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[3,4-b]pyridinyl. Heteroaryl in the context of the invention preferably represents a monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom. The following may be mentioned by way of example and by way of preference: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
Mono-(Ci-C4)-alkylamino in the context of the invention means an amino group with one straight-chain or branched alkyl substituent which contains 1 , 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, for example.
Di-(Ci-C4)-alkylamino in the context of the invention means an amino group with two identical or different straight-chain or branched alkyl substituents which each contain 1 , 2, 3 or 4 carbon atoms, such as: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-methylamino, N-isopropyl-N-n-propylamino, NN-diisopropylamino, N-n-butyl-N-methyl- amino, and N-tert-butyl-N-methylamino, for example.
(Ci-C4)-Alkylcarbonyl in the context of the invention means a straight-chain or branched alkyl group having 1 , 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carbonyl group [- C(=0)-], such as: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, and pivaloyl, for example.
(Ci-C4)-Alkoxycarbonyl in the context of the invention means a straight-chain or branched alkoxy group having 1 , 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carbonyl group [- C(=0)-], such as: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, and tert-butoxycarbonyl, for example.
Mono-(Ci-C4)-alkylaminocarbonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a carbonyl group [-C(=0)-] and which has one straight-chain or branched alkyl substituent having 1 , 2, 3 or 4 carbon atoms, such as: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, and tert-butylaminocarbonyl, for example.
Di-(Ci-C4)-alkylaminocarbonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a carbonyl group [-C(=0)-] and which has two identical or different straight- chain or branched alkyl substituents having in each case 1 , 2, 3 or 4 carbon atoms, such as: NN- dimethylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n- propylaminocarbonyl, N-isopropyl-N-methylaminocarbonyl, NN-diisopropylaminocarbonyl, N-n-butyl- N-methylaminocarbonyl, and N-teri-butyl-N-methylaminocarbonyl, for example.
An oxo substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond
In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g. : tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
The term "C1-C4", as used in the present text, e.g. in the context of the definition of "Ci-C i-alkyl" or "Ci-C i-alkoxy", means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3, or 4 carbon atoms.
The term "Ci-Ce", as used in the present text, e.g. in the context of the definition of "Ci-C6-alkyl", means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.
Further, as used herein, the term "C3-C6", as used in the present text, e.g. in the context of the definition of "C3-C6-cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.
Further, as used herein, the term "C3-C8", as used in the present text, e.g. in the context of the definition of "C3-C8-cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.
When a range of values is given, said range encompasses each value and sub-range within said range. For example:
"C1-C4" encompasses Ci, C2, C3, C4, G-C4, C1-C3, C1-C2, C2-C4, C2-C3, and C3-C4;
"C1-C3" encompasses Ci, C2, C3, C1-C3, C1-C2, and C2-C3;
"C2-C4" encompasses C2, C3, C4, C2-C4, C2-C3, and C3-C4;
"C3-C6" encompasses C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
As used herein, the term "leaving group" means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy (mesyl(ate), Ms), [(trifluoromethyl)sulfonyl]oxy (triflyl/(ate), Tf), [(nonafluoro- butyl)sulfonyl]oxy (nonaflate, Nf), (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromo- phenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)- sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [( -tert- butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.
It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
The term "Isotopic variant" of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The term "Isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The expression "unnatural proportion" means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.
Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium),
UC, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 123I, 124I, 125I, 129I and 131I, respectively.
With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3H or 14C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or UC may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefmic bonds (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131 ; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and acetylenic bonds (N. H. Khan, J. Am. Chem. Soc, 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron Letters, 2011, 52, 3865) is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons (J. G. Atkinson et al., US Patent 3966781). A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R. P. Hanzlik et al., Biochem. Biophys. Res. Commun. 160, 844, 1989; P. J. Reider et al., J. Org. Chem. 52, 3326-3334, 1987; M. Jarman et al., Carcinogenesis 16(4), 683-688, 1995; J. Atzrodt et al., Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., Chem. Commun. 2000, 1519-1520; K. Kassahun et al., WO2012/112363.
The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490; A. Streitwieser et al., J. Am. Chem. Soc, 1963, 85, 2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641 ; C. L. Perrin, et al., J. Am. Chem. Soc, 2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102; D. J. Kushner et al., Can. J. Physiol. Pharmacol., 1999, 77, 79). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound's pharmacokinetic/ pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium- containing compounds of general formula (I) having a certain pattern of one or more deuterium- hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
In another embodiment the present invention concerns a deuterium-containing compound of general formula (I) having 1, 2, 3 or 4 deuterium atoms, particularly with 1, 2 or 3 deuterium atoms.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11 -30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, it is possible for the compounds of the present invention to exist as tautomers. For example, any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 3H tautomer, or even a mixture in any amount of the two tautomers, namely :
Figure imgf000016_0001
1 H tautomer 3H tautomer
The present invention includes all possible tautomers of the compounds of the present invention single tautomers, or as any mixture of said tautomers, in any ratio. The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, terra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt, in particular as a free acid. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2- hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, NN-dimethyl-glucamine, N-ethyl-glucamine, 1 ,6-hexanediamine, glucosamine, sarcosine, serinol, 2- amino- 1 ,3 -propanediol, 3-amino-l ,2-propanediol, 4-amino-l ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(«-propyl)ammonium, tetra(«-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.
In accordance with a preferred embodiment of the first aspect, the present invention covers a pharmaceutically acceptable salt of compounds of general formula (I), (I-C), supra, which is an alkali metal salt, in particular a sodium or potassium salt, or an ammonium salt derived from an organic tertiary amine, in particular choline.
Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HC1", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.
As used herein, the term "in vivo hydrolysable ester" means an in vivo hydro lysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci-Ce alkoxymethyl esters, e.g. methoxymethyl, Ci-Ce alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-Ci-C6 alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; l ,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-l ,3-dioxolen-2-onylmethyl ; and Ci-C6-alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, it being possible for said esters to be formed at any carboxy group in the compounds of the present invention.
An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethyl- propionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
Preference is given to compounds of the formula (I) in which
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000019_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13, R18, R22 and R: represent a hydrogen atom, a halogen atom, (Ci-C i)-alkyl, trifluoromethyl, amino, hydroxyl or cyano,
R14, R19, R23 and R: represent a hydrogen atom, a halogen atom, (Ci-C i)-alkyl, amino, hydroxy, cyano, (Ci-C i)-alkoxycarbonyl, (Ci-C i)-alkoxy, difluoroalkoxy or trifluoromethoxy, where said (Ci-C4)-alkyl is optionally substituted with up to three fluorine atoms,
R15, R20 and R2 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl, amino or hydroxy, R16, R25 and R: represents a hydrogen atom, a halogen atom, (Ci-C4)-alkyl, amino, hydroxy, cyano, (Ci-C4)-alkoxycarbonyl, (Ci-C4)-alkoxy, difluoromethoxy or trifluoromethoxy,
where said (Ci-C4)-alkyl is optionally substituted with up to three fluorine atoms,
R17, R21 and R29 represents a hydrogen atom, a halogen atom, (Ci-C4)-alkyl, trifluoromethyl, amino, hydroxyl or cyano,
or
lH-pyrazol-4-yl,
where lH-pyrazol-4-yl is optionally substituted, identically or differently, with one or two groups selected from (Ci-C4)-alkyl, trifluoromethyl, difluoromethyl, amino, hydroxyl and cyano,
R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom, methyl and ethyl,
R5 represents a group selected from a hydrogen atom, methyl and ethyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring or an oxetane ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5- yl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, 2-oxa-5-azabicyclo[2.2.2]oct-5-yl, 4-methylpiperazin-l -yl, 4-ethylpiperazin-l -yl, 4-cyclopropylpiperazin-l -yl, 4-isopropylpiperazin-l -yl, 4- isobutylpiperazin-1 -yl, 6-methyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-ethyl-3,6- diazabicyclo[3.1.1 ]hept-3-yl, 6-cyclopropyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-isopropyl-3,6- diazabicyclo[3.1.1 ]hept-3-yl, 6-isobutyl-3,6-diazabicyclo[3.1.1]hept-3-yl, 5-methyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl, 5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 5-isopropyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl, 5-isobutyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 5-cyclopropyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 8-ethyl-3,8- diazabicyclo[3.2.1 ]oct-3-yl, 8-cyclopropyl-3,8-diazabicyclo[3.2.1 ]oct-3-yl, 8-isopropyl-3,8- diazabicyclo [3.2.1 ] oct-3 -yl, 8-isobutyl-3 , 8-diazabicyclo [3.2.1] oct-3 -yl, 5-methyl-2,5- diazabicyclo[2.2.2]oct-2-yl, 5-ethyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5-isopropyl-2,5- diazabicyclo[2.2.2]oct-2-yl, 5-isobutyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5-cyclopropyl-2,5- diazabicyclo[2.2.2]oct-2-yl, -7-azabicyclo[3.3.1]non-7-yl, 7-methyl-3,7- diazabicyclo[3.3.1 ]non-3-yl, 7-ethyl-3,7-diazabicyclo[3.3.1 ]non-3-yl,l ,4-oxazepan-4-yl, 7- cyclopropyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 7-isopropyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 7- isobutyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 1 ,4-oxazepan-4-yl, 4-methyl-l ,4-diazepan-l -yl, 4-ethyl- 1 ,4-diazepan-l -yl , 4-cyclopropyl-l ,4-diazepan-l -yl, 4-isopropyl-l ,4-diazepan-l -yl, 4-isobutyl- 1 ,4-diazepan-l -yl or (Ci-C4)-alkoxycarbonylamino,
wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, 2-oxa-5-azabicyclo[2.2.2]oct-5-yl, 4-methylpiperazin-l -yl, 4- ethylpiperazin-1 -yl, 4-cyclopropylpiperazin-l -yl, 4-isopropylpiperazin-l -yl, 4-isobutylpiperazin- 1 -yl, 6-methyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-ethyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6- cyclopropyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-isopropyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6- isobutyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 5-methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl, 5-ethyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl, 5-isopropyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl, 5-isobutyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl, 5-cyclopropyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl, 8-methyl-3,8- diazabicyclo [3.2.1 ] oct-3 -yl, 8 -ethyl-3 , 8-diazabicyclo [3.2.1 ] oct-3 -yl, 8 -cyclopropyl-3 , 8 - diazabicyclo[3.2.1 ]oct-3-yl, 8-isopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 8-isobutyl-3,8- diazabicyclo[3.2.1 ]oct-3-yl, 5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5-ethyl-2,5- diazabicyclo[2.2.2]oct-2-yl, 5-isopropyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5-isobutyl-2,5- diazabicyclo[2.2.2]oct-2-yl, 5-cyclopropyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 3-oxa-7- azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 7-ethyl-3,7- diazabicyclo[3.3.1 ]non-3-yl,l ,4-oxazepan-4-yl, 7-cyclopropyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 7- isopropyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 7-isobutyl-3,7-diazabicyclo[3.3.1 ]non-3-yl, 1 ,4- oxazepan-4-yl, 4-methyl-l ,4-diazepan-l -yl, 4-ethyl-l ,4-diazepan-l -yl , 4-cyclopropyl-l ,4- diazepan-l -yl, 4-isopropyl-l ,4-diazepan-l -yl, 4-isobutyl-l ,4-diazepan-l -yl are optionally substituted, identically or differently, with one or two groups selected from hydroxy, methyl, difluoromethyl and trifluoromethyl,
R7 represents a group selected from trifluoromethoxy, difluoromethoxy, methoxymethyl, 2,2,2- trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
R8 represents a hydrogen atom or fluorine,
R9 represents a hydrogen atom or fluorine,
R10 represents a hydrogen atom or fluorine,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Preference is also given to compounds of the formula (I) in which
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000022_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13, R18, R22 and R26 represent a hydrogen atom, fluorine or methyl,
R14, R19, R23 and R27 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15, R20 and R24 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R16, R25 and R28 represent a hydrogen atom,
R17 and R21 represent a hydrogen atom,
R29 represents a hydrogen atom, fluorine or methyl,
or
1 -methyl- 1 H-pyrazol-4-yl,
R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom and methyl,
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo-
[3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl,
4-methylpiperazin-l -yl, 6-methyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 8-methyl-3,8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl or 1 ,4-oxazepan-4-yl are optionally substituted with methyl,
R7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
R8 represents a hydrogen atom,
R9 represents a hydrogen atom,
R10 represents a hydrogen atom,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Particular preference is also given to compounds of the formula (I) in which
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000023_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 and R18 represent a hydrogen atom, fluorine or methyl,
R14 and R19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15 and R20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R16 represents a hydrogen atom,
R17 and R21 represent a hydrogen atom,
R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom and methyl,
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 1 ,4-oxazepan-4-yl or 4-methyl-l ,4-diazepan-l -yl are optionally substituted with methyl,
R7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
R8 represents a hydrogen atom,
R9 represents a hydrogen atom,
R10 represents a hydrogen atom, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Particular preference is also given to compounds of the formula (I) in which
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000024_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 and R18 represent a hydrogen atom, fluorine or methyl,
R14 and R19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15 and R20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R16 represents a hydrogen atom,
R17 and R21 represent a hydrogen atom,
with the provisio that no more than one of R13, R14, R15 is different from hydrogen, with the provisio that no more than one of R18, R19 and R20 is different from hydrogen,
R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom and methyl,
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 1 ,4-oxazepan-4-yl or 4-methyl-l ,4-diazepan-l -yl are optionally substituted with methyl,
R7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
R8 represents a hydrogen atom,
R9 represents a hydrogen atom,
R10 represents a hydrogen atom,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Preference is also given to compounds of the formula (I) in which
R1 represents a hydrogen atom,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R1 represents fluorine,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R2 represents group of the formula,
Figure imgf000026_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 and R18 represent a hydrogen atom, fluorine or methyl,
R14 and R19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15 and R20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R16 represents a hydrogen atom,
R17 and R21 represent a hydrogen atom,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R2 represents group of the formula,
Figure imgf000026_0002
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 and R18 represent a hydrogen atom, fluorine or methyl,
R14 and R19 represent a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15 and R20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R16 represents a hydrogen atom,
R17 and R21 represent a hydrogen atom,
with the provisio that no more than one of R13, R14, R15 is different from hydrogen,
with the provisio that no more than one of R18, R19 and R20 is different from hydrogen, and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same. Preference is also given to compounds of the formula (I) in which
R2 represents group of the formula,
Figure imgf000027_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 represents a hydrogen atom, fluorine or methyl,
R14 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15 represents a hydrogen atom,
R16 represents a hydrogen atom,
R17 represents a hydrogen atom,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of
Preference is also given to compounds of the formula (I) in which
R2 represents group of the formula,
Figure imgf000027_0002
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 represents a hydrogen atom, fluorine or methyl,
R14 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R15 represents a hydrogen atom,
R16 represents a hydrogen atom, R17 represents a hydrogen atom,
with the provisio that no more than one of R13 and R14 is different from hydrogen,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R2 represents group of the formula,
Figure imgf000028_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R18 represents a hydrogen atom, fluorine or methyl,
R19 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R20 represents a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R21 represent a hydrogen atom,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of
Preference is also given to compounds of the formula (I) in which
R2 represents group of the formula,
Figure imgf000028_0002
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R18 represents a hydrogen atom, fluorine or methyl,
R19 represents a hydrogen atom, chlorine, fluorine, (Ci-C4)-alkoxycarbonyl or methyl,
R20 represents a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R21 represent a hydrogen atom, with the provisio that no more than one of R18, R19 and R20 is different from hydrogen, and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R3 represents represents a hydrogen atom,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R3 represents represents a fluorine,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R4 represents a group selected from a hydrogen atom and methyl,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen, or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 4-methyl-l ,4-diazepan-l -yl, 1 ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino, wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin- 1 -yl, 6-methyl-3 ,6-diazabicyclo [3.1.1 ]hept-3 -yl, 8-methyl-3 , 8- diazabicyclo[3.2.1]oct-3-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl, 7-methyl-3,7-diazabicyclo- [3.3.1]non-3-yl, 1 ,4-oxazepan-4-yl or 4-methyl-l,4-diazepan-l-yl are optionally substituted with methyl,
and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
Preference is also given to compounds of the formula (I) in which
R6 represents morpholin-4-yl or 4-methylpiperazin- 1-yl,
wherein morpholin-4-yl or 4-methylpiperazin- 1-yl are optionally substituted with methyl, and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading "further embodiments of the first aspect of the present invention".
The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
In accordance with a second aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra, said methods comprising the step
[A] of allowing an intermediate compound of general formula (II)
Figure imgf000030_0001
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and,
X represents chlorine, bromine, iodine or triflate,
to react in the presence of a suitable inert solvent, with a compound of general formula (III)
Figure imgf000031_0001
(ΠΙ),
in which R4 and R5 are as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (IV)
Figure imgf000031_0002
(IV),
in which R1, R3, R4, R5, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst, with an amine of general formula (V),
11
R
HN.
(V),
in which R11 and R12 are as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (VI)
Figure imgf000031_0003
(VI), in which R1, R3, R4, R5, R7, R8, R9, R10, R11 and R12 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst and a suitable base, with a boronic acid derivative of general formula (VII- A) or in the presence of a suitable Iridium-catalyst and a suitable base with a boronic acid derivative of general formula (VII-B),
Figure imgf000032_0001
thereby giving a compound of general formula (VIII)
Figure imgf000032_0002
(VIII),
in which R1, R3, R4, R5, R7, R8, R9, R10, R11 and R12 are as defined for the compound of general formula (I) as defined supra,
which is allowed to react in the presence of a suitable base and in the presence of a suitable catalyst, with a compound of general formula (IX),
R2
(ix),
in which
X1 represents chlorine, bromine, iodine, mesylate, triflate or tosylate,
thereby giving a compound of general formula (I), then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
or
[B] of allowing an intermediate compound of general formula (II)
Figure imgf000033_0001
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
to react in the presence of a suitable inert solvent and where appropiate in the presence of a suitable base and where appropriate in the presence of a suitable amide coupling reagent, with a compound of general formula (X)
Figure imgf000033_0002
(X),
in which R4, R5 and R6 are as defined for the compound of general formula (I) as defined supra, and
X2 represents chlorine or hydroxy,
thereby giving a compound of general formula (VI),
which is then allowed to react according to the steps shown in [A] to give a compound of general formula (I),
or [C] of allowing an intermediate compound of general formula (II)
Figure imgf000034_0001
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst, and a suitable base, with a boronic acid derivative of general formula (VII- A) or in the presence of a suitable Iridium-catalyst and a suitable base with a boronic acid derivative of general formula (VII-B),
Figure imgf000034_0002
thereby giving a compound of general formula (XI)
Figure imgf000034_0003
(xi),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra,
which is allowed to react in the presence of a suitable base and in the presence of a suitable catalyst, with a compound of general formula (IX),
R2
X1
(ix),
in which represents chlorine, bromine, iodine, mesylate, inflate or tosylate,
thereby giving a compound of general formula (XII)
Figure imgf000035_0001
(XII),
in which R1, R2, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra,
to react in the presence of a suitable inert solvent and where appropiate in the presence of a suitable base and where appropriate in the presence of a suitable amide coupling reagent, with a compound of general formula (X)
Figure imgf000035_0002
(X),
in which R4, R5 and R6 are as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (I),
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
or
[D] of allowing an intermediate compound of general formula (II)
Figure imgf000035_0003
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst, with a boronic acid derivative of general formula (VII-C),
Figure imgf000036_0001
in which R2 is as defined for the compound of general formula (I) as defined supra,
thereby giving a compound of general formula (XII)
Figure imgf000036_0002
(XII),
in which R1, R2, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra,
which is then allowed to react according to the steps shown in [C] to give a compound of general formula (I),
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
The compounds of the formulae (III), (V), (VII), (IX) and (X) are commercially available, known from the literature or can be prepared analogously to processes known from the literature. The compounds of the formulae (X) can be prepared from the corresponding carboxylic acids analogously to processes known from the literature.
The preparation processes described can be illustrated in an exemplary manner by the synthesis schemes below (Schemes 1 to 5):
Figure imgf000037_0001
Figure imgf000037_0002
[a): Toluene, rt; b): triethylamin, potassium iodide, DMF, 100°C: c): PdCl2(dppf)*CH2Cl2, potassium acetate, dioxane, 50°C:; d): PdCl2(dppf)*CH2Cl2, potassium carbonate, water, DMF, 1,2- dimethoxyethane 80 °C].
Scheme 2:
Figure imgf000038_0001
Figure imgf000038_0002
[a): pyridine, dichloromethane, rt; b): PdCl2(dppf)*CH2Cl2, potassium acetate, dioxane, 80 °C; c): PdCl2(dppf)*CH2Cl2, potassium carbonate, water, DMF, 1,2-dimethoxyethane 80°C].
Scheme 3 :
Figure imgf000039_0001
Figure imgf000039_0002
[a): PdCl2(dppf)*CH2Cl2, potassium acetate, dioxane, 80°C; b): PdCl2(dppf)*CH2Cl2, potassium carbonate, water, DMF, 1 ,2-dimethoxyethane 80°C; c): pyridine, rt].
Scheme 4:
Figure imgf000040_0001
[a): T3P, Pyridine, dioxane, 105°C; b): PdCl2(dppf)*CH2Cl2, potassium carbonate, water, DMF, 1,2- dimethoxyethane 80°C].
Scheme 5:
Figure imgf000040_0002
[a): T3P, Pyridine, 50°C; b): PdCl2(dppf)*CH2Cl2, potassium carbonate, water, DMF, 1,2- dimethoxyethane 80°C].
The present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in schemes 1, 2 and 3 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition in Procedures [A], [B] and [C], interconversion of any of the substituents, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, T1, T2 and X can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
Suitable inert solvents for the process steps (II) + (III)→ (IV) and (II) + (X)→ (VI) and (XII) + (X)→ (I) aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, diisopropyl - ether, methyl tert-butyl ether, 1,2-dimethoxyethane, bis-(2-methoxyethyl) ether, tetrahydrofuran or 1,4- dioxane, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2- dichloroethane, trichloroethylene or chlorobenzene or dipolar aprotic solvents such as acetonitrile, NN- dimethylformamide (DMF), NN-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), NN- dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (ΝΜΡ) or pyridine. It is also possible to use mixtures of the solvents mentioned, optionally also in a mixture with water. Preference is given to using dichloromethane .
Suitable bases for the process step (II) + (III)→ (IV) and (II) + (X)→ (VI) and (XII) + (X)→ (I) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, if appropriate with addition of an alkali metal iodide, for example sodium iodide or potassium iodide, alkali alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethyl- amine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine, pyridine, 4-(NN- dimethylamino)pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,4-diazabicyclo[2.2.2]octane (DABCO®). Preference is given to using pyridine.
The process steps (II) + (III)→ (IV) and (II) + (X)→ (VI) and (XII) + (X)→ (I) are generally carried out in a temperature range of from -10°C to +220°C, preferably in a range from +10°C to +150°C. However, it is also possible to carry out the reaction at reduced or at elevated pressure (for example at from 0.5 to 5 bar). It may optionally be advantageous to carry out the reaction with microwave irradiation. Inert solvents for the amine coupling (IV) + (V)— »■ (VI) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulphoxide, NN-dimethylformamide, NN-dimethylacetamide, NN'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents. Suitable bases for the process step (IV) + (V)— »■ (VI) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, if appropriate with addition of an alkali metal iodide, for example sodium iodide or potassium iodide, alkali alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine, pyridine, 4-(NN-dimethylamino)pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1 ,4-diazabicyclo- [2.2.2]octane (DABCO®). Preference is given to using NN-diisopropylethylamine.
Suitable catalysts for the process step (IV) + (V)— »■ (VI) are alkali metal iodides, for example sodium iodide, potassium iodide, sodium bromide, potassium bromide, tetrabutylammonium iodide, tetrabutylammonium bromide and DMAP. Preference is given to using potassium iodide.
The amine coupling (IV) + (V)—> (VI) is generally conducted within a temperature range from -20°C to +150°C, preferably at 0°C to +100°C. The conversion can be effected at standard, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, standard pressure is employed. It may optionally be advantageous to carry out the reaction with microwave irradiation.
Suitable inert solvents for the process steps (VI) + (VII)→(VIII) and (VIII) + (IX)→(I) and (II) + (VII) —> (XI) and (XI) + (IX)—> (XII) are aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, bis-(2- methoxyethyl) ether, tetrahydrofuran or 1,4-dioxane, or dipolar aprotic solvents such as acetonitrile, NN-dimethylformamide (DMF), NN-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), NN- dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) or pyridine. It is also possible to use mixtures of the solvents mentioned, optionally also in a mixture with water. Preference is given to using 1 ,2-dimethoxyethane, 1, 2 -dimethoxy ethane in a mixture with water, dimethylformamide, 1,4-dioxane and N-methylpyrrolidinone.
Suitable bases for the process step (VI) + (VII)→(VIII) and (VIII) + (IX)→(I) and (II) + (VII)→ (XI) and (XI) + (IX)—> (XII) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, if appropriate with addition of an alkali metal iodide, for example sodium iodide or potassium iodide, alkali alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert- butoxide, alkali metal acetates such as sodium acetate or potassium acetate, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethyl- amine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine, pyridine, 4-(NN- dimethylamino)pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,4-diazabicyclo[2.2.2]octane (DABCO®). Preference is given to using NN-diisopropylethylamine and potassium acetate.
Suitable Palladium catalysts for the process (VI) + (VII)→(VIII) and (VIII) + (IX)→(I) and (II) + (VII) —> (XI) and (XI) + (IX)—> (XII) are, for example, palladium on activated carbon, palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenyl- phosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complex, optionally in conjunction with additional phosphane ligands, for example 1,4- Bis(diphenylphosphino)butane-palladium(II) chloride (Pd(dppb)Cb); Dichloro[l,3- bis(diphenylphosphino)propane]palladium(II) (Pd(dppp)Ch), [1,1 '-Bis(diphenyl- phosphino)ferrocene]dichloropalladiu (Pd(dppf)Cl2, 2,2'-bis(diphenylphosphino)-l,l '-binaphthyl (ΒΓΝΑΡ), (2-biphenyl)di-tert-butylphosphine, dicyclohexyl[2',4',6'-tris(l-methylethyl)biphenyl-2- yl]phosphane (XPhos), bis(2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (Xantphos) [cf, for example, Hassan J. et al., Chem. Rev. 2002, 102, 1359-1469], 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-l, -biphenyl (BrettPhos), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos), 2-(di-t-butylphosphino)-3 -methoxy-6-methyl-2 ' ,4 ' ,6 ' -tri-i-propyl- 1,1 '- biphenyl (RockPhos) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-ButylXPhos). It is furthermore possible to use appropriate precatalysts such as chloro-[2-(dicyclohexylphosphine)-3,6- dimethoxy-2',4',6'-triisopropyl-l , 1 '-biphenyl] [2-(2-aminoethyl)-phenyl]palladium(II) (BrettPhos precatalyst) [cf., for example, S. L. Buchwald et al., Chem. Sci. 2013, 4, 916], optionally in combination with additional phosphane ligands such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'- triisopropyl-l,r-biphenyl (BrettPhos); preference is given to bis(dibenzylideneacetone)palladium(0) in combination with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and chloro-[2- (dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-l, -biphenyl] [2-(2-aminoethyl)phenyl]- palladium(II) (BrettPhos precatalyst) or a mixture of chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy- 2',4',6'-triisopropyl-l, -biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalyst) and 2- (dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-l, -biphenyl (BrettPhos).
The process steps (VI) + (VII)→(VIII) and (VIII) + (IX)→(I) and (II) + (VII)→ (XI) and (XI) + (IX) —> (XII) are generally carried out in a temperature range of from +10°C to +220°C, preferably from +20°C to +150°C, at atmospheric pressure. However, it is also possible to carry out the reaction at reduced or at elevated pressure (for example at from 0.5 to 5 bar). It may optionally be advantageous to carry out the reaction with microwave irradiation.
The compounds of the formula (II) are known from the literature or can be prepared by reacting a compound of the formula (XIII),
Figure imgf000044_0001
in which R1 and R3 are as defined for the compound of general formula (I) as defined supra and,
X represents chlorine, bromine, iodine or triflate,
and
T3 represents tert-butyl,
to react in the presence of a suitable inert solvent, with an amine of general formula (XIV)
Figure imgf000044_0002
in which R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (XV),
Figure imgf000045_0001
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and,
X represents chlorine, bromine, iodine or triflate,
and
T3 represents tert-butyl,
the protecting group T3 is detached in a suitable inert solvent by methods known to those skilled in the art, and the resulting compound of the formula (XVI)
Figure imgf000045_0002
is allowed to react with a suitable reducing agent to reduce the nitro group to an amino group, thereby giving compounds of the formulae (II) that are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
The process described is illustrated in an exemplary manner by the scheme below (Scheme 4):
Scheme 4:
Figure imgf000046_0001
[a): PYBOP, diisopropylamine, DMF, r.t; b): formic acid, reflux; c): TiCl3, HC1, water, THF, 25-30 °C].
Starting materials are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the Experimental Section. Inert solvents for the amide coupling (XIII) + (XIV)— »■ (XV) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulphoxide, NN-dimethylformamide, NN-dimethylacetamide, NN'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents. Suitable condensing agents for the amide formation (XIII) + (XIV) —> (XV) are, for example, carbodiimides such as NN'-diethyl-, NN'-dipropyl-, NN'-diisopropyl-, NN'-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CD I), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l,2- oxazolium 3-sulphate or 2-teri-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2- ethoxy-l-ethoxycarbonyl-l ,2-dihydroquinoline or isobutyl chloro formate, propanephosphonic anhydride (T3P), l -chloro-NN,2-trimethylprop-l -ene-l -amine, diethyl cyanophosphonate, bis(2-oxo-3- oxazolidinyl)phosphoryl chloride, benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 0-(benzotriazol-l -yl)-N,NN'N'-tetramethyluronium tetrafluoroborate (TBTU), O-(benzotriazol-l -yl)- NNN'.N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-l -(2H)-pyridyl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (TPTU), 0-(7-azabenzotriazol-l-yl)-N,NN',N'- tetramethyluronium hexafluorophosphate (HATU) or 0-(lH-6-chlorobenzotriazol-l -yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with further auxiliaries such as 1 -hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and also as bases alkali metal carbonates, for example sodium carbonate or potassium carbonate or sodium hydrogencarbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for example triethylamine, N- methylmorpholine, N-methylpiperidine or NN-diisopropylethylamine or pyridine. Preference is given to using PYBOP. The condensation (XIII) + (XIV)—> (XV) is generally conducted within a temperature range from - 20°C to +100°C, preferably at 0°C to +60°C. The conversion can be effected at standard, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, standard pressure is employed.
Alternatively, the carboxylic acid of the formula (XIII) can also first be converted to the corresponding carbonyl chloride and the latter can then be reacted directly or in a separate reaction with an amine of the formula (XIV) to the compounds of the invention. The formation of carbonyl chlorides from carboxylic acids is effected by the methods known to those skilled in the art, for example by treatment with thionyl chloride or oxalyl chloride, in the presence of a suitable base, for example in the presence of pyridine, and optionally with addition of dimethylformamide, optionally in a suitable inert solvent.
Suitable inert solvents for the process step (XV)— »(XVI) for example, are formic acid and tri-(Ci-C4 )- alkoxy-(Ci-C i)-alkyls. Preference is given to using formic acid.
The process (XV)— »(XVI) is generally carried out in a temperature range of from +60°C to +180°C, preferably from 30°C to +100°C.
Suitable inert solvents for the process step (XVI)— »(II) for example, are water or alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, esters like ethyl acetate or butyl acetate, carboxylic acids like acetic acid, ethers such as diethyl ether, diisopropyl ether, methyl teri-butyl ether, 1,2-dimethoxyethane, bis-(2-methoxyethyl) ether, tetrahydrofuran or 1,4-dioxane, or dipolar aprotic solvents such as acetonitrile, NN-dimethylformamide (DMF), NN-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) or pyridine. It is also possible to use mixtures of the solvents mentioned, optionally also in a mixture with water. Preference is given to using alcohols or mixtures of water and tetrahydrofuran.
Suitable reducing agents for the process step (XVI)— »(II) are for example Tin(II) chloride, Titanium (III) chloride, Iron(III) chloride, Titanium(TV) chloride, Tin, Iron, Zinc, Indium, Aluminum, Nickel, ; preference is given to Tin(II) chloride and Titanium (III) chloride. The process (XVI)— >(U) is generally carried out in a temperature range of from -80°C to +220°C, preferably from -10°C to +100°C.
Further compounds according to the invention can optionally also be prepared by converting functional groups of individual substituents, in particular those listed under R2 and R6, starting with the compounds of the formula (I) obtained by the above processes. These conversions are carried out by customary methods known to the person skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carboxamides, and also the introduction and removal of temporary protective groups.
The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art. Detailed procedures can also be found in the Experimental, in the section on the preparation of the starting compounds and intermediates.
The compounds of the invention have valuable pharmacological properties and can be used for prevention and treatment of diseases in humans and animals.
The compounds of the invention are potent, chemically stable inhibitors of Wnt/ -catenin signaling and are therefore suitable for treatment and/or prevention of disorders and pathological processes, especially those in which of the Wnt/ -catenin signaling is involved in the course of acute or chronic respiratory diseases and cardio-respiratory diseases and/or hyperproliferative disorders.In the context of the present invention, these especially include inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
The present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular inflammatory and fibrotic pulmonary disorders and cardio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer. Lung diseases occur as a result of tissue damage to the lung (epithelium, parenchyma, vasculature, etc.), which could be caused by different genetic predispositions, infectious or non-infectious acute and chronic stimuli (including but not limited to viruses, bacteria, parasites, fungi, drugs, toxins, smoke, aerosols, allergens, mechanical injury, radiation, etc.). This leads to the stimulation of host-defense, homeostatic control and tissue repairing mechanisms and pathways including Wnt/ -catenin signaling, which govern biological processes such as: cell-cell adhesion, inflammation, immune system regulation, stem cell maintenance, re-epithelialization, cell fate determination, cell polarity, division, proliferation, differentiation, migration, angiogenesis, apoptosis, epithelial-mesenchymal transition (EMT), fibroblast- to-myo fibroblast differentiation fibroblast activation, connective tissue synthesis, would healing, fibrosis. (Am J Respir Cell Mol Biol. 2010 Jan;42(l):21 -31). If the homeostatic balance in the injured tissue is not successfully restored, the dysregulation and aberrant activation of Wnt/ -catenin signaling (Nat Med. 2016 Feb; 22(2): 154-162) could result in pathogenic events such as uncontrolled inflammation, angiogenesis, cellular proliferation, abnormal cell cycling/survival signals, fibrosis (J Exp Med. 2011 Jul 4; 208(7): 1339-1350), tumor formations, eventually leading to organ(s) failure and death. Non-limiting examples of such acute and chronic lung diseases and conditions resulting from aberrant activation ofWnt/ -catenin signaling include:
• Idiopathic Fibrotic Disorders of the Lung: Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (UIP), Acute Interstitial Pneumonitis (Hamman-rich Syndrome), Familial
Pulmonary Fibrosis, Respiratory Bronchiolitis/Desquamative Interstitial Pneumonitis, Cryptogenic Organizing Pneumonia, Nonspecific Interstitial Pneumonia, Lymphocytic Interstitial Pneumonia, Autoimmune Pulmonary Fibrosis
• Primary ILDs: Sarcoidosis, Pulmonary Langerhans Cell Histiocytosis (Eosinophilic Granuloma), Amyloidosis, Pulmonary Vasculitis, Lymphangioleiomyomatosis (+/- Tuberous
Sclerosis), ARDS-related, AIDS-related, Bone Marrow Transplantation-related, Post-Infection, Eosinophilic Pneumonia, Alveolar Proteinosis, Diffuse Alveolar Hemorrhage Syndromes, Pulmonary Veno-Occlusive Disease, Alveolar Microlithiasis, Metastatic Calcification
• Connective Tissue Disease-Related Interstitial Lung Disease (ILDs): Scleroderma/Systemic Sclerosis ILD, Polymyositis-Dermatomyositis ILD, Systemic Lupus Erythematosus ILD, Rheumatoid Arthritis ILD, Mixed Connective Tissue Disease ILD, Primary Sjogren Syndrome ILD, Ankylosing Spondylitis ILD
• Hereditary & Other ILDs: Gaucher Disease, Niemann -Pick Disease, Hermansky-Pudlak Syndrome, Neurofibromatosis, Aspiration, Exogenous Lipoid Pneumonia, Lymphangitic Carcinomatosis, Pulmonary Lymphoma
• Occupational/Environmental ILDs: Silicosis, Asbestosis, Hard-Metal / Coal Workers' Pneumoconiosis, Berylliosis, Siderosis (Arc Welder) / Stannosis (Tin), Hypersensitivity Pneumonitis, Bird Breeder's Lung & Farmer's Lung
• Drug-Induced ILDs
· Different forms of lung cancer (Nat Rev Cancer. 2013 Jan;13(l): l l -26) - e.g. but not limited to small-cell and non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma
• Pulmonary Arterial Hypertension (Drug Discov Today. 2014 Aug;19(8): 1270-6)
• Asthma, Allergic Airway Diseases, Rhinitis (Expert Opin Ther Targets. 2014 Sep; 18(9): 1023- 34)
· Nasal mucosal infections and polyps (drug-induced rhinitis, vasomotor rhinitis and season- dependent allergic rhinitis, hay fever)
• COPD and pulmonary emphysema (PLoS One. 2011 ; 6(9): e25450)
• Combined pulmonary fibrosis and emphysema (CPFE)
• Chronic inflammatory cough, Iatrogenic cough, chronic persistent cough
· Cystic Fibrosis
• Various conditions and diseases associated with acute lung inflammation
• Lung transplant failure/rejection (J Clin Invest. 2017 Feb 27)
• Bronchiolitis obliterans
• Mechanical ventilation-induced and various other forms of acute lung injury (Intensive Care Med. 2011 Jul;37(7):1201 -9)
• Bronchopulmonary dysplasia (BPD) (Am J Physiol Lung Cell Mol Physiol. 2017 Feb 1 ;312(2):L186-L195)
• Hyperoxia-induced neonatal lung injury (Pediatric Research (2013) 73, 719-725) The compounds and compositions provided herein can be further used for prevention or treatment of numerous diseases related to abnormalities in the Wnt signaling cascade such as but not limited to: cardiovascular and heart diseases; autoimmune diseases; hematopoietic disorders; neurological diseases; gynecological disorders; renal diseases; obesity and metabolism-related disorders; infections; eye and ear diseases; hair growth disorders and other conditions with abnormal Wnt signaling. The Wnt-β- catenin signaling pathway has been implicated in the embryogenesis of the joints, muscles and bone and is one of the main pathways to maintain the musculoskeletal homeostasis in adults (Nat Med. 2013 Feb; 19(2): 179-92). The compounds according to the invention are also suitable for the treatment and/or prophylaxis of diseases related to a number of musculoskeletal and bone pathological disorders including but not limited to rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, high bone mass disorders, osteogenic tumors, osteosarcomas, Ewing's sarcoma, Pyle's disease, musclular dystrophy, muscular fibrotic diseases, polymyositis (PM), dermatomyositis (DM), Duchenne muscular dystrophy (DMD) (J Clin Neurol. 2016 Jul;12(3):351-60)
The compounds and compositions according to the invention can be further used for prevention or treatment of prophylaxis and treatment of diseases and conditions associated with abnormal regulation of other signaling cascades that Wnt/ -catenin signaling has been shown to regulate or cross-talk with and/or in which Wnt/ -catenin signaling inhibition could be beneficial and of therapeutic potential. Non- limiting examples of such signaling pathways include Notch, FGF (fibroblast growth factor), EGF (epidermal growth factor), HGF, SHH (Sonic hedgehog), Hippo pathways, transforming growth factor (TGF)- , Hedgehog (Hh), Notch, ErbB signaling and others (Breast Cancer Res. 2011 Jun 10;13(3):211).
The compounds and compositions provided herein can be also used to treat various hyperproliferative disorders (Nat Rev Cancer. 2013 Jan;13(l): l 1 -26). Wnt/ -catenin signaling regulates cell growth, differentiation and angiogenesis, therefore irregular activation of this pathway increases the risk of malignant transformation in many cell types, tissues and organs, but also is linked to promotion of metastasis and resistance to chemotherapy (Genes & Diseases (2016) 3, l le40). Hereby, the inhibitors of the Wnt/ -catenin signaling provided according to this invention offer new therapeutic avenues to treat a large variety of hyperproliferative disorders and their complications that include but are not limited to the following: psoriasis, keloids, hyperplasias affecting the skin; solid tumors; breast tumors (incl. but not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ and lobular carcinoma in situ); lung and respiratory tract tumors (incl. but not limited to small-cell carcinoma, non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma); brain tumors (incl. but not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal and pineal tumor); tumors of the male and fermale reproductive organs (incl. but not limited to benign prostate hyperplasia, prostate cancer, testicular cancer, endometrial, cervical, ovarian, vaginal, and vulvar cancer, uterine sarcomas); tumors of the digestive tract (incl. but not limited to anal, colon, polyposis coli, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers); tumors of the urinary tract (incl. but not limited to urothelial cell carcinoma, bladder, penile, kidney, renal pelvis, ureter, urethral and papillary renal cancers); tumors of the eye (incl. but not limited to intraocular melanoma, retinoblastoma); liver cancers (incl. but not limited to hepatocellular carcinoma, cholangiocarcinoma, intrahepatic bile duct carcinoma, mixed hepatocellular cholangiocarcinoma), skin cancers (incl. but not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer); head and neck cancers (incl. but not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer, thyroid, parathyroid and their distant metastases); Lymphomas (incl. but not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system); sarcomas (incl. but not limited to soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma); leukaemias (incl. but not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia); bone and skeletal muscle tumors
In the context of the present invention, the terms "prevention" or "prophylaxis" are used synonymously and refer to the prevention or reduction of the risk to develop, experience or suffer from such conditions and/or their associated symptoms.
In the context of the present invention, the term "treatment" or "treating" includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states. The term "therapy" is understood here to be synonymous with the term "treatment". The terms "prevention", "prophylaxis" and "preclusion" are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.
The treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
In accordance with a further aspect, the present invention thus further provides for the use of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders.
In accordance with a further aspect, the present invention further provides for the use of the compounds according to the invention for production of a medicament for treatment and/or prevention of disorders, especially of the aforementioned disorders.
In accordance with a further aspect, the present invention further provides a medicament comprising at least one of the compounds according to the invention for treatment and/or prevention of disorders, especially of the aforementioned disorders. In accordance with a further aspect, the present invention further provides for the use of the compounds according to the invention in a method for treatment and/or prevention of disorders, especially of the aforementioned disorders.
In accordance with a further aspect, the present invention further provides a method of treatment and/or prevention of disorders, especially of the aforementioned disorders, using an effective amount of at least one of the compounds according to the invention.
In accordance with a further aspect, the compounds of general formula (I), as described supra, or stereoisomers, tautomers, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, are suitable for the treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
In accordance with a further aspect, the present invention thus further provides for the use of the compounds according to the invention for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
In accordance with a further aspect, the present invention further provides for the use of the compounds according to the invention for production of a medicament for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
In accordance with a further aspect, the present invention further provides a medicament comprising at least one of the compounds according to the invention for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
In accordance with a further aspect, the present invention further provides for the use of the compounds according to the invention in a method for treatment and/or prevention of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer. In accordance with a further aspect, the present invention further provides a method of treatment and/or prevention of disorders, especially of inflammatory and fibrotic pulmonary disorders and cardiopulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer, using an effective amount of at least one of the compounds according to the invention.
It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),
• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),
• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),
• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),
• isotonicity agents (for example glucose, sodium chloride),
• adsorbents (for example highly-disperse silicas),
• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)),
• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),
• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)), • capsule materials (for example gelatine, hydroxypropylmethylcellulose),
• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
• penetration enhancers,
• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),
• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),
• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
An embodiment of the invention are pharmaceutical compositions comprising at least one compound of formula (I) according to the invention, preferably together with at least one inert, non-toxic, pharmaceutically suitable auxiliary, and the use of these pharmaceutical compositions for the above cited purposes.
In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and car dio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
The term "combination" in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts. A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
A non- fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. The invention also relates to pharmaceutical compositions containing at least one of the compounds according to the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the abovementioned diseases.
Suitable combinations could be for example but not limited to:
Serine / threonine / tyrosine kinase inhibitors such as but not limited to, preferably Nintedanib, Regorafenib, Imatinib, Gefitinib, Erloinib, Sorafenib, Dasatinib, Sunitinib, Nilotinib, Lapatinib, Pazotinib, Ruxolitinib, Crizotinib, Vemurafenib, Vandetanib, Ponatinib, Cabozantinib, Tofacitinib, Bosutinib, Axitinib, Ibrutinib, Afatinib, Dabrafenib, Trametinib, Idelalisib, Ceritinib, Lentavatinib, Palbocicnib;
Antifibrotic agents, such as but not limited to, preferably Pirfenidone, adenosine A2b receptor antagonists, sphingosine 1 -phosphate receptor 3 (S1P3) antagonists, autotaxin inhibitors, lysophosphatidic acid receptors 1 (LPA- 1) and lysophosphatidic acid receptor 2 (LPA-2) antagonists, FP receptor antagonists, lysylxidase (LOX) inhibitors, lysyl oxidase-like-2 inhibitors, CTGF inhibitors, IL-13 antagonists, TGF-β antagonists, av integrin antagonists, CCR2 antagonists;
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with supplement oxygen therapy;
Anti-obstructive or anti-inflammatory agents for the treatment of chronic obstructive pulmonary disease (COPD), asthma or other respiratory conditions such as but not limited to, short-acting bronchodilators for example albuterol, levalbuterol, ipratropium, albuterol/ipratropium; corticosteroids, for example fluticasone, budesonide, prednisolone; methylxanthines, for example theophylline; long-acting bronchodilators (long-acting β2 agonists, muscarinic antagonists), for example aclidinium, arformoterol, formoterol, glycopyrrolate, indacaterol, olodaterol, salmeterol, tiotropium, tiotropiumbromid, umeclidinium; combination drugs, for example glycopyrrolate/formoterol, glycopyrrolate/indacaterol, tiotropium/olodaterol, umeclidinium/vilanterol, budesonide/ formoterol, fluticasone/salmeterol, fluticasone/vilanterol); phosphodiesterase-4 inhibitors, for example roflumilast; used inhalatively or systemically;
Prostacyclin analogs-based vasodilators, for example epoprostenol, beraprost, iloprost, treprostinil, selexipag;
Endothelin receptor antagonists, for example bosentan, darusentan, macitentan, sitaxsentan and ambrisentan;
Organic nitrates and NO donors, such as, for example, sodium nitroprusside, nitroglycerol, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as, for example, inhibitors of the phospho diesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE5 inhibitors, for example Sildenafil, vardenafil, tadalafil, ureafil, dasantafil, avanafil, mirodenafil or lodenafil;
Soluble guanylate cyclase (sGC) stimulators and activators - heme-dependent, for example riociguat, vericiguat and heme-independent activators;
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium channel blockers, for example amlodipine, diltiazem, verapamil, nifedipine;
Blood pressure-lowering active substances, for example and preferably from the group of angiotensin All antagonists, for example losaran, candesartan, valsartan, telmisartan, emburdenan, irbesartan, olmesartan, eprosartan or azilartartan or a dual angiotensin All antagonists / NEP inhibitor, such as and preferably LCZ696 valsartan/sacubitrile, ACE inhibitors, for example enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, for example aliskiren, SPP-600 or SPP-800, β- blockers, for example propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, Nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or buccololol, a-receptor blocker , for example prazosin, mineralocorticide receptor antagonists, for example spironolactone, eplerenone or finerenone and diuretics, for example furosemid, bumetanid, torsemid, bendroflumethiazid, chlorthiazid, hydrochlorthiazid, hydroflumethiazid, methyclothiazid, polythiazid, trichlormethiazid, chlorthalidon, indapamid, metolazon, quinethazon, acetazolamid, dichlorphenamid, methazolamid, glycerin, isosorbid, mannitol, amilorid, triamteren; In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin or proprotein convertase subtilisin/kexin type 9 (PCSK9) blockers, for example evolocumab, bococizumab, alirocumab, petidomimetics, PCSK9 antisense oligonucleotide;
Antiarrhythmic agents that interfere with the sodium (Na+) channel, anti-sympathetic nervous system agents, agents that affect potassium (K+) efflux, agents affect calcium channels and the AV node, agents that work by other mechanisms;
Anticoagulants, antiplatelets, fibrinolytic agents and low molecular weight (LMW)-heparin derivatives, for example vitamin K antagonists, for example coumarins and non-coumarin 1,3-indandione derivatives; heparin (UFH) and low-molecular-weight heparins (LMW), for example tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (Ml 18) and EP-42675/ORG42675; direct thrombin inhibitors (DTI) such as, for example, Pradaxa (dabigatran), atecegatran (AZD-0837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanogitran (BIBT-986 and prodrug BIBT-1011), hirudin; direct factor Xa inhibitors, for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX- 9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux, substances which inhibit the aggregation of platelets (platelet aggregation inhibitors, thrombocyte aggregation inhibitors), such as, for example, acetylsalicylic acid (such as, for example, aspirin), P2Y12 antagonists such as, for example, ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor, elinogrel, PAR-1 antagonists such as, for example, vorapaxar, PAR-4 antagonists, EP3 antagonists such as, for example, DG041 ; platelet adhesion inhibitors such as GPVI and/or GPIb antagonists such as, for example, Revacept or caplacizumab; fibrinogen receptor antagonists (glycoprotein-IIb/IIIa antagonists), for example abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;
Anti-inflammatory, immunomodulating, immunosuppressive and / or cytotoxic agents, for example systemic or inhaled corticosteroids, non-steroidal anti-inflammatory drugs, as well as acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, steroids, azithromycin, pirfenidone or etanercept;
Synthetic and biological disease-modifying antirheumatic drugs (DMARDs) - e.g. abatacept, adalimumab, azathioprine, chloroquine and hydroxychloroquine, ciclosporin (Cyclosporin A), D- penicillamine, etanercept, golimumab, gold salts, infliximab, leflunomide, methotrexate, minocycline, rituximab, sulfasalazine (SSZ); Antagonists of growth factors, cytokines and chemokines, exemplarily and preferentially antagonists of TGF-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17, IL-33 and integrins;
Chemotherapeutic agents such as, e.g. for the therapy of neoformations (neoplasia) of the lungs or other organs;
Compounds which influence the energy metabolism of the heart, such as, for example, etomoxir, dichloroacetate, ranolazine or trimetazidine;
Drugs which inhibit human neutrophil elastase (HNE), prolyl endopetidase (PREP) or matrix metalloproteinases (MMPs), particularly inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (e.g. MMP-1, MMP-3, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11, and MMP-13) and the metalloelastase (MMP- 12);
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as, for example, and preferably ezetimibe, tiqueside or pamaqueside;
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example, and preferably orlistat.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, for example, and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide;
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP-Inhibitor (Torcetrapib, JJT-705 or CETP-vaccine), thyroid receptor agonists (D-Thyroxin, 3,5,3'-Triiodothyronin (T3), CGS 23425 or Axitirome), squalene synthase inhibitors, AC AT inhibitoren, MTP inhibitors, PPAR-α-, PPAR-γ- and/or PPAR-8-agonists, cholesterol absorption inhibitors, polymeric bovine acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists;
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with compounds which block the binding of serotonin to its receptor, examples and preferably antagonists of the 5-HT2B receptor;
In combination with Rho kinase inhibitory compounds, such as, for example, and preferably Fasudil, Y 27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with proton pump inhibitors (PPIs) such as omeprazole, aspirin and omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole, esomeprazole magnesium/naproxen, omeprazole/sodium bicarbonate.
The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known agents of the same indication treatment group, such as agents used for the treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio -pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.In a particular preferred embodiment of the invention, the inventive compounds are administered in combination with one or more further agents selected from the group of serine / threonine / tyrosine kinase inhibitors and/or antifibrotic agents.
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day, and more preferably from about 0.01 mg/kg to about 10 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. The average daily oral dosage regimen will preferably be from 0.01 to 30 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Nevertheless, it may optionally be necessary to deviate from the stated amounts, namely depending on body weight, route of administration, individual response to the active substance, type of preparation and time point or interval when application takes place. Thus, in some cases it may be sufficient to use less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. When applying larger amounts, it may be advisable to distribute these in several individual doses throughout the day.
According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once or twice or three times a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once or twice a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once a day. For the oral administration, a rapid release or a modified release dosage form may be used.
EXPERIMENTAL SECTION
A. Examples
The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.
Table 1: Abbreviations and acronyms:
Figure imgf000062_0001
Ex. Example
d day(s)
TLC thin-layer chromatography
DCI direct chemical ionization (in MS)
DIEA NN-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
DMSO dimethyl sulphoxide
eq. equivalent(s)
ESI electrospray ionization (in MS)
h hour(s)
HATU 0-(7-azabenzotriazol-l -yl)-N,NN',N'-tetramethyluronium hexafluorophosphate
HPLC high-pressure, high-performance liquid chromatography
HV high vacuum
LC/MS liquid chromatography-coupled mass spectroscopy
LDA lithium diisopropylamide
min minute(s)
MS mass spectroscopy
MTBE Methyl-tert-butyl ether
NMR nuclear magnetic resonance spectroscopy
PYBOP (benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate) quant. Quantitative RP reversed phase (in HPLC)
RT room temperature
Rt retention time (in HPLC)
THF Tetrahydrofuran
T3P 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)
Other abbreviations not specified herein have their meanings customary to the skilled person.
The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
EXPERIMENTAL SECTION - GENERAL PART
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
The 'H-NMR data of selected compounds are listed in the form of 'H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δι (intensityi), 82 (intensity2), ... , δ; (intensity), ... , δη (intensity^.
The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 'H-NMR peaklist is similar to a classical 'H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 'H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 'H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Isolera autopurifier (Biotage) and eluents such as gradients of e.g. hexane/ EE or dichloromethane/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
The percentage yields reported in the following examples are based on the starting component that was used in the lowest molar amount. Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentrated in vacuum" refers to use of a Buchi rotary evaporator at a minimum pressure of approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (°C). In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety. Methods
HPLC, LC-MS and GC methods:
Method 1 : Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 μ 50 mm x 1 mm; mobile phase A: 1 1 of water + 0.25 ml of 99% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A→ 1.2 min 5% A → 2.0 min 5% A; oven: 50°C; flow rate: 0.40 ml/min; UV detection: 208-400 nm.
Method 2: Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 μ 50 mm x 1 mm; mobile phase A: 1 1 of water + 0.25 ml of 99% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 95% A→ 6.0 min 5% A → 7.5 min 5% A; oven: 50°C; flow rate: 0.35 ml/min; UV detection: 210-400 nm.
Method 3: MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; column: Agient ZORBAX Extend-C18 3.0 mm x 50 mm 3.5 micron; mobile phase A: 1 1 of water + 0.01 mol of ammonium carbonate, mobile phase B: 1 1 of acetonitrile; gradient: 0.0 min 98% A→ 0.2 min 98% A → 3.0 min 5% A→ 4.5 min 5% A; oven: 40°C; flow rate: 1.75 ml/min; UV detection: 210 nm.
Method 4: Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 μ 50 mm x 2.1 mm; mobile phase A: 1 1 of water + 0.25 ml of 99% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A→ 0.3 min 90% A→ 1.7 min 5% A→ 3.0 min 5% A; oven: 50°C; flow rate: 1.20 ml/min; UV detection: 205-305 nm.
Method 5: Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m x 200 μιη x 0.33 μιη; constant helium flow rate: 1.20 ml/min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C/min→ 300°C (maintained for 3.33 min).
Method 6: MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1 mm x 75 mm, C18 1.8 μιη; mobile phase A: 1 1 of water + 0.01%) formic acid; mobile phase B: 1 1 of acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B→ 2.5 min 95% B→ 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210 nm/ Optimum Integration Path 210-300 nm.
Method 7: Instrument: Waters Single Quad MS System; Instrument Waters UPLC Acquity; Column : Waters BEH CI 8 1.7 μιη 50 x 2.1 mm; Eluent A: 1 1 water + 1.0 mL (25% ammonia)/L, Eluent B: 1 1 acetonitrile; Gradient: 0.0 min 92% A→ 0.1 min 92% A→ 1.8 min 5% A→ 3.5 min 5% A; Oven: 50°C; Flow: 0.45 niL/min; UV-Detection: 210 nm (208-400 nm)
Method 8: Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m x 200 μιη x 0.33 μιη; constant helium flow rate: 1.20 ml/min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C/min→ 300°C (maintained for 3.33 min).
Method 9: Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25- 2 MM; eluent A: water + 0.0375 vol %> trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol %> trifluoroacetic acid; gradient: 0-0.8 min, 5-95%> B, 0.8-1.2 min 95%> B; flow 1.5 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.
Method 10: Instrument: Hewlett Packard HP 1100 Series CS Multikrom 100-3 system; column: 60 mm x 4.6 mm, CI 8 5 μπι; mobile phase A: acetonitrile + 1 % formic acid; mobile phase B: water + 1 % formic acid; gradient: 0.0 min 20% A→ 8.0 min 80% A→ 10.0 min 90% A; oven: 35°C; flow rate: 1. 0 ml/min; UV detection: 254 nm.
Method 11 : Instrument: SHIMADZU LCMS-2020; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B, 1.2-1.21 min 5% B, 1.21 -1.55 min 5% B; flow 1.5 ml/min; temperature: 50 °C; UV detection: 220 nm & 254 nm.
Method 12: Instrument: SHIMADZU LCMS-2020; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 0-60% B, 0.8-1.2 min 60% B, 1.2-1.21 min 0% B, 1.21 -1.55 min 0%) B; flow 1.5 ml/min; temperature: 50 °C; UV detection: 220 nm & 254 nm.
Microwave: The microwave reactor used was a "single-mode" instrument of the Emrys™ Optimizer type.
When compounds according to the invention are purified by preparative HPLC by the above-described methods in which the eluents contain additives, for example trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art. In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process. Unless specified in more detail, additions to names and structural formulae, such as "hydrochloride", "trifluoroacetate", "sodium salt" should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.
This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and/or purification processes described.
Synthetic Intermediates Intermediate 1
tert-Butyl (5-bromo-2- {[3-nitro-4-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate
Figure imgf000069_0001
4-bromo-2-[(tert-butoxycarbonyl)amino]benzoic acid (99.5 g, 315 mmol), PYBOP (246 g, 472 mmol), 3-nitro-4-(trifluoromethoxy)aniline (97.9 g, 441 mmol) and N,N-diisopropylethylamine (160 ml, 940 mmol) were dissolved in N,N-dimethylformamide (1.3 1, 16 mol) and stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate and pH was adjusted to 5 with IN aqueous hydrochloric acid. The organic phase was separated and the aqueous one was extracted twice more with ethyl acetate. The combined organic layers were first washed with water and then with brine. The solution was evaporated under reduced pressure and the residue was chromatographed over silica gel with petrol ether/ethyl acetate 9: 1. This yielded 72.6 g of the product (44% yield).
LC-MS (Method 4): Rt = 1.71 min; MS (ESIneg): m/z = 520 [M-H]" Intermediate 2
7-Bromo -3 - [3 -nitro -4 -(trifluoromethoxy)phenyl] quinazolin
Figure imgf000070_0001
tert-butyl (5-bromo-2- {[3-nitro-4-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate (72.6 g, 140 mmol) was dissolved in formic acid (220 ml, 5.8 mol) and this mixture was refluxed for 3 hours. The reaction mixture was then poured over water and the pH was adjusted to pH 8 with 33% aqueous solution of sodium hydroxide. The suspension was filtered, the solid was washed with water and dried under vacuum to provide 58.7 g (95 % purity, 93 % yield) of the product.
LC-MS (Method 6): Rt = 2.11 min; MS (ESIpos): m/z = 432 [M+H]+
Intermediate 3
3 - [3 -Amino-4-(trifluoromethoxy)phenyl] -7-bromoquinazolin
Figure imgf000070_0002
7-bromo-3-[3-nitro-4-(trifluoromethoxy)phenyl]quinazolin-4(3H)-one (10.0 g, 96% purity, 22.3 mmol) was dissolved in 280 mL tetrahydroiuran and cooled to 0-5°C. Titanium(III) trichloride solution in 2N aqueous hydrochloric acid (140 ml, 20 % purity, 220 mmol, 10 eq.) was added under stirring while keeping the temperature below 10°C. After completing the addition the mixture was stirred at rt for 3 h, when full conversion was observed. Ethyl acetate (300 mL) was added and under cooling (0°C) and strong stirring the reaction mixture was neutralized by addition of solid sodium carbonate. The mixture was stirred for further 10 min and then the supernatant was decanted and filtered through a short pad of celite. The remaining material (solids) was stirred with 200 mL ethyl acetate for 30 min and then decanted and filtered analogously. The two organic fractions were then combined, dried over magnesium sulfate, filtered and evaporated. The residue was then suspended in 30 mL MTBE and sonicated. The suspension was filtered and the solid was washed with few milliliters of MTBE and then dried under vacuum to provide 7.28 g, (95% purity, 77% yield) of the title product.
LC-MS (Method 6): Rt = 1.93 min; MS (ESIpos): m/z = 400 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.41), 0.008 (2.52), 1.157 (0.83), 1.175 (1.72), 1.193 (0.86), 1.356 (3.75), 1.988 (3.17), 2.183 (0.52), 2.328 (0.57), 2.367 (0.49), 2.524 (1.80), 2.670 (0.57), 2.711 (0.47), 4.021 (0.78), 4.038 (0.73), 5.745 (10.59), 6.673 (4.21), 6.679 (4.40), 6.694 (4.47), 6.701 (4.73), 6.900 (8.74), 6.906 (8.25), 7.264 (3.59), 7.267 (3.64), 7.285 (3.36), 7.289 (3.20), 7.752 (4.27), 7.757 (4.32), 7.773 (4.71), 7.778 (4.87), 7.960 (7.26), 7.964 (7.05), 8.096 (8.56), 8.117 (7.57), 8.373 (16.00).
Intermediate 4
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide
Figure imgf000071_0001
l-(morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (CAS 1257236-65-9) (858 mg, 4.13 mmol) was suspended in dichloromethane (46 ml) and l -chloro-N,N,2-trimethylprop-l -en- 1 -amine (760 μΐ, 96 % purity, 5.5 mmol) was added. This mixture was stirred at rt for 16 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (46 ml) and the mixture was once more evaporated. The residue was then suspended in dichloromethane (46 ml) and pyridine (330 μΐ, 4.1 mmol) and 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (580 mg, 95 % purity, 1.38 mmol) were added. This reaction mixture was stirred for 3 days at rt. The mixture was quenched by addition of water and extractive work-up was performed, washing the organic phase twice with water and once with brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 100:0 to 50:50 to provide 730 mg (94% yield) of the title product.
LC-MS (Method 6): Rt = 2.23 min; MS (ESIpos): m/z = 553 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.107 (2.89), 1.119 (8.11), 1.127 (9.08), 1.137 (4.14), 1.157 (0.60), 1.175 (1.13), 1.193 (0.54), 1.224 (0.43), 1.266 (3.89), 1.276 (9.00), 1.283 (7.63), 1.296 (2.98), 1.398 (1.95), 1.988 (1.71), 2.328 (0.49), 2.452 (8.37), 2.463 (12.14), 2.473 (9.19), 2.670 (0.49), 3.700 (12.06), 4.021 (0.43), 4.039 (0.41), 7.402 (4.10), 7.409 (4.08), 7.424 (4.63), 7.430 (4.70), 7.688 (3.75), 7.691 (3.79), 7.710 (3.30), 7.713 (3.13), 7.763 (4.30), 7.767 (4.41), 7.784 (4.78), 7.789 (5.00), 7.975 (7.65), 7.979 (7.38), 8.096 (8.60), 8.117 (7.57), 8.408 (16.00), 8.550 (7.95), 8.557 (7.90), 10.613 (7.97).
Intermediate 5
l-(Moφholin-4-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}cyclopropanecarboxamide
Figure imgf000072_0001
An argon stream was passed through a mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(morpholin-4-yl)cyclopropanecarboxamide (482 mg, 85% purity, 736 μιηοΐ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (206 mg, 810 μιηοΐ) and potassium acetate (217 mg, 2.21 mmol) in dioxane (7.4 ml) for 5 min. l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (36.1 mg, 44.2 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 1 h. The reaction mixture was then filtered through celite, rinsing twice the filter cake with dioxane. The filtrate was evaporated and dried under high vacuum. The residue was used in the next step without further purification. 686 mg of the title product was obtained (64 % purity, 99 % yield).
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.069 (0.79), 1.159 (16.00), 1.167 (2.12), 1.295 (0.48), 1.348 (3.34), 1.893 (0.78), 3.568 (1.90). Intermediate 6
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-chloropropanamide
(Racemate)
Figure imgf000073_0001
A suspension of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (4.50 g, 96 % purity, 10.8 mmol) in toluene (140 ml) was slowly treated with 2-chloropropanoyl chloride (racemate, 1.6 ml, 97 % purity, 16 mmol) and stirred for 2 h at 100°C. The reaction mixture was then let to cool down to rt and the mixture was evaporated. The residue was suspended in 40 mL of MTBE and stirred for 10 min. The suspension was then filtered and the solid was washed with additional 10 mL MTBE. The solid was dried under high vacuum to provide 5.47 g (99 % yield) of the title product.
LC-MS (Method 6): Rt = 2.06 min; MS (ESIpos): m/z = 490 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.603 (15.81), 1.620 (16.00), 2.340 (0.52), 4.904 (1.27), 4.921 (4.12), 4.938 (4.07), 4.954 (1.26), 5.469 (0.93), 7.506 (2.89), 7.512 (2.96), 7.528 (3.81), 7.534 (3.97), 7.649 (3.42), 7.651 (3.54), 7.670 (2.61), 7.673 (2.58), 7.768 (3.38), 7.772 (3.69), 7.789 (3.76), 7.794 (4.06), 7.981 (5.95), 7.985 (6.20), 7.999 (0.59), 8.105 (7.84), 8.108 (7.55), 8.115 (6.24), 8.126 (5.99), 8.414 (0.41), 8.442 (12.22), 10.371 (5.68).
Intermediate 7
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (Racemate)
Figure imgf000074_0001
A solution of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- chloropropanamide (racemate) (900 mg, 96 % purity, 1.76 mmol) in N,N-dimethylformamide (5.5 ml) was treated with triethylamine (740 μΐ, 5.3 mmol), morpholine (460 μΐ, 5.3 mmol) and potassium iodide (58.5 mg, 352 μιηοΐ) and stirred at 50°C for 16 h. The reaction mixture was then partitioned between 30 mL of water and 60 mL of ethyl acetate and extractive work-up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 100:0 to 50:50. The material obtained was submitted to a second chromatography over silica gel under the same conditions to provide finally the title product. 580 mg (59 % yield).
LC-MS (Method 6): Rt = 1.86 min; MS (ESIpos): m/z = 541 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.157 (0.56), 1.175 (1.27), 1.190 (15.81), 1.207 (16.00), 1.988 (1.78), 2.570 (4.56), 2.588 (1.80), 2.598 (1.06), 2.670 (0.48), 3.373 (1.32), 3.391 (4.31), 3.408 (4.23), 3.426 (1.26), 3.641 (7.22), 3.651 (12.66), 3.662 (7.20), 4.021 (0.43), 4.038 (0.44), 7.421 (3.13), 7.427 (3.21), 7.443 (3.78), 7.449 (3.89), 7.663 (3.47), 7.684 (2.83), 7.767 (3.20), 7.771 (3.44), 7.788 (3.66), 7.792 (4.00), 7.980 (5.05), 7.983 (5.19), 8.103 (6.56), 8.124 (5.86), 8.400 (6.15), 8.406 (6.35), 8.415 (12.35), 10.084 (6.87).
Intermediate 8
2-(Morpholin-4-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000075_0001
An argon stream was passed through a mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-2-(morpholin-4-yl)propanamide (racemate) (1.19 g, 2.20 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (613 mg, 2.41 mmol) and (646 mg, 6.59 mmol) potassium acetate in (22 ml) dioxane for 5 min. l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethan-complex (108 mg, 132 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 4 h. The reaction mixture was then filtered through celite, rinsing the filter cake with dioxane. The filtrate was evaporated at 40°C and dried under high vacuum to provide 1.83 g (70 % purity, 99 % yield) of the title product. The material was used in the next step without further purification.
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.070 (1.08), 1.159 (16.00), 1.168 (2.88), 1.190 (1.45), 1.207 (1.39), 1.352 (9.84), 3.568 (3.58), 3.641 (0.67), 3.652 (1.07), 3.663 (0.60), 7.845 (0.42), 7.920 (1.26), 7.972 (0.69), 8.198 (0.54), 8.217 (0.48), 8.388 (1.11), 8.399 (0.55), 8.406 (0.51), 10.086 (0.60).
Intermediate 9
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)propanamide (racemate)
Figure imgf000075_0002
A solution of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- chloropropanamide (racemate) (250 mg, 96% purity, 489 μηιοΐ) in N,N-dimethylformamide (1.5 ml) was treated with triethylamine (200 μΐ, 1.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (166 mg, 1.47 mmol) and potassium iodide (16.2 mg, 97.8 μιηοΐ) and stirred at 50°C for 16 h. The reaction mixture was then partitioned between 6 mL of water and 20 mL of ethyl acetate and extractive work -up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate 100:0 to 50:50 to provide 95.0 mg (34 % yield) of the title product.
LC-MS (Method 6): Rt = 2.16 min; MS (ESIpos): m/z = 567 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.57), 1.149 (14.41), 1.157 (6.08), 1.166 (15.12), 1.175 (8.63), 1.193 (3.93), 1.398 (1.47), 1.798 (4.44), 1.809 (3.16), 1.826 (1.00), 1.844 (0.66), 1.910 (1.04), 1.935 (3.07), 1.952 (1.88), 1.966 (1.89), 1.980 (2.73), 1.988 (14.55), 2.005 (0.83), 2.451 (10.70), 2.581 (10.88), 3.282 (1.21), 3.299 (4.48), 3.333 (1.34), 4.003 (1.08), 4.021 (3.25), 4.039 (3.22), 4.056 (1.10), 4.260 (5.22), 4.265 (5.24), 5.754 (16.00), 7.423 (3.30), 7.430 (3.42), 7.445 (3.89), 7.452 (4.11), 7.655 (3.03), 7.659 (3.25), 7.677 (2.59), 7.681 (2.59), 7.765 (3.36), 7.770 (3.64), 7.787 (3.75), 7.791 (4.19), 7.978 (5.47), 7.982 (5.67), 8.103 (6.76), 8.124 (6.06), 8.415 (13.12), 8.429 (6.39), 8.436 (6.40), 9.711 (6.78).
Intermediate 10
2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000076_0001
An argon stream was passed through a mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanamide (racemate) (95.0 mg, 167 μιηοΐ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (46.8 mg, 184 μιηοΐ) and potassium acetate (49.3 mg, 502 μιηοΐ) in dioxane (1.7 ml) for 5 min. l,l-Bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethan-complex (8.20 mg, 10.0 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 1 h. The reaction mixture was then filtered through celite, rinsing twice the filter cake with dioxane. The filtrate was evaporated and dried under high vacuum to yield 150 mg (67 % purity, 98 % yield) of the title product. The material was used in the next step without further purification. Intermediate 11
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(6-oxa-3- azabicyclo [3.1.1 ]hept-3 -yl)propanamide (racemate)
Figure imgf000077_0001
A solution of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- chloropropanamide (racemate) (250 mg, 96% purity, 489 μιηοΐ) in N,N-dimethylformamide (1.5 ml) was treated with triethylamine (200 μΐ, 1.5 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane (145 mg, 1.47 mmol) and potassium iodide (16.2 mg, 97.8 μιηοΐ) and stirred at 50°C for 24 h. After cooling, the reaction mixture was then partitioned between 6 mL of water and 25 mL of ethyl acetate and extractive work-up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 100:0 to 50:50 to provide finally the title product. 63.0 mg (23 % yield).
LC-MS (Method 6): Rt = 1.79 min; MS (ESIpos): m/z = 553 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), -0.008 (5.68), 0.008 (6.30), 0.146 (0.68), 1.175 (0.56), 1.292 (15.82), 1.309 (16.00), 1.988 (0.95), 2.328 (4.82), 2.348 (4.02), 2.670 (1.12), 2.917 (12.87), 2.930 (3.55), 2.950 (2.93), 2.966 (1.33), 2.979 (3.13), 3.006 (4.91), 3.072 (3.93), 3.096 (2.13), 3.100 (2.10), 3.540 (1.24), 3.557 (4.41), 3.575 (4.38), 3.592 (1.27), 4.470 (5.12), 4.485 (5.06), 7.428 (3.46), 7.434 (3.52), 7.450 (4.11), 7.456 (4.32), 7.639 (3.16), 7.643 (3.25), 7.661 (2.63), 7.665 (2.60), 7.767 (3.67), 7.772 (3.84), 7.788 (4.11), 7.793 (4.50), 7.981 (5.44), 7.985 (5.32), 8.104 (7.25), 8.126 (6.54), 8.344 (5.86), 8.351 (5.91), 8.420 (13.55), 9.851 (6.68). Intermediate 12
2-(6-Oxa-3-azabicyclo[3.1.1]hept-3-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000078_0001
An argon stream was passed through a mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)propanamide (racemate) (63.0 mg, 114 μιηοΐ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (31.8 mg, 125 μιηοΐ) and potassium acetate (33.5 mg, 342 μmol) in dioxane (1.1 ml) for 5 min. l,l -Bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethan-complex (5.58 mg, 6.83 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 1 h. The reaction mixture was then filtered through celite, rinsing twice the filter cake with dioxane. The filtrate was evaporated and dried under high vacuum to provide 110 mg (60% purity, 96% yield) of the title product. The material was used in the next step without further purification. Intermediate 13
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(4-methylpiperazin-l - yl)cyclopropanecarboxamide
Figure imgf000078_0002
l-(4-Methylpiperazin-l-yl)cyclopropanecarboxylic acid hydrochloride (WO2014147021A2, Intermediate 42) (2.48 g, 11.2 mmol) was suspended in dichloromethane (40 ml) and l -chloro-N,N,2- trimethylprop-l -en-l-amine (2.0 ml, 15 mmol) was added. This mixture was stirred at rt for 2 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (40 ml) and the mixture was once more evaporated and dried under high vacuum. The residue was then suspended in dichloromethane (40 ml) and pyridine (910 μΐ, 11 mmol) and 3-[3-amino-4-(trifluoromethoxy)phenyl]- 7-bromoquinazolin-4(3H)-one (1.58 g, 95 % purity, 3.75 mmol) were added. This reaction mixture was stirred for lh at rt. The mixture was quenched by addition of water and extractive work-up was performed, washing the organic phase three times with water. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 100:0 to 90: 10 to provide 1.91 g (88% yield) of the title product.
LC-MS (Method 6): Rt = 1.25 min; MS (ESIpos): m/z = 566 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.73), -0.008 (6.02), 0.146 (0.74), 1.160 (7.82), 1.169 (4.39), 1.213 (4.12), 1.222 (7.91), 1.243 (2.43), 2.328 (0.88), 2.367 (0.71), 2.670 (3.96), 2.710 (2.87), 2.997 (1.01), 5.754 (16.00), 7.460 (2.54), 7.482 (3.08), 7.674 (4.01), 7.696 (3.19), 7.768 (4.58), 7.772 (4.82), 7.789 (4.99), 7.794 (5.35), 7.981 (7.80), 7.985 (7.76), 8.097 (8.83), 8.118 (7.71), 8.304 (0.98), 8.403 (15.87), 10.226 (0.68).
Intermediate 14
l-(4-methylpiperazin-l-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin- 3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide
Figure imgf000079_0001
An argon stream was passed through a mixture N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(4-methylpiperazin-l-yl)cyclopropanecarboxamide (530 mg, 88 % purity, 823 μιηοΐ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (230 mg, 906 μιηοΐ) and potassium acetate (242 mg, 2.47 mmol) in dioxane (8.3 ml) for 5 min. l,l-Bis-(diphenylphosphino)- ferrocen]-dichloropalladium-dichloromethan-complex (40.3 mg, 49.4 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 3 h. The reaction mixture was then filtered through celite, rinsing twice the filter cake with dioxane. The filtrate was evaporated and dried under high vacuum to provide 940 mg (53 % purity, 99 % yield) of the title product. The material was used in the next step without further purification.
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.069 (1.12), 1.110 (0.49), 1.117 (0.55), 1.159 (16.00), 1.243 (0.51), 1.296 (0.70), 1.349 (7.95), 1.905 (1.10), 2.192 (1.90), 3.566 (12.51), 3.568 (14.37), 7.967 (0.57), 8.380 (0.64), 8.598 (0.47), 8.605 (0.47), 10.650 (0.40).
Intermediate 15
N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(4-methylpiperazin-l - yl)propanamide (racemate)
Figure imgf000080_0001
A solution of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-chloro- propanamide (racemate) (2.50 g, 96 % purity, 4.89 mmol) in N,N-dimethylformamide (15 ml, 200 mmol) was treated with triethylamine (2.0 ml, 15 mmol), 1 -methylpiperazine (1.6 ml, 15 mmol) and potassium iodide (162 mg, 978 μιηοΐ) and stirred at 50°C for 16 h. The reaction mixture was then evaporated at 40°C and the residue was partitioned between 30 mL of water and 150 mL of ethyl acetate. Extractive work-up was performed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was stirred with MTBE for 1 h, filtered and dried. The solid was then purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 100:0 to 93:7 to provide 1.40 g (50 % yield) of the title product.
LC-MS (Method 6): Rt = 1.25 min; MS (ESIpos): m/z = 554 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.69), -0.008 (6.49), 0.008 (7.34), 0.146 (0.69), 1.174 (8.29), 1.192 (8.43), 2.177 (16.00), 2.327 (0.99), 2.402 (1.15), 2.670 (0.71), 3.392 (0.71), 3.409 (2.36), 3.427 (2.29), 3.444 (0.63), 7.402 (1.96), 7.408 (1.99), 7.424 (2.23), 7.430 (2.31), 7.660 (1.73), 7.663 (1.80), 7.681 (1.52), 7.685 (1.47), 7.767 (2.10), 7.772 (2.20), 7.788 (2.34), 7.793 (2.53), 7.980 (3.27), 7.984 (3.25), 8.104 (4.02), 8.125 (3.58), 8.417 (7.60), 8.482 (3.37), 8.488 (3.40), 10.141 (3.51). Intermediate 16
2-(4-Methylpiperazin-l-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin- 3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000081_0001
An argon stream was passed through a mixture N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-2-(4-methylpiperazin-l-yl)propanamide (racemate) (1.14 g, 95% purity, 1.95 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (546 mg, 2.15 mmol) and potassium acetate (575 mg, 5.86 mmol) in dioxane (20 ml) for 5 min. l,l -Bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethan-complex (95.7 mg, 117 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 3 h. The reaction mixture was then filtered through celite, rinsing twice the filter cake with dioxane. The filtrate was evaporated and dried under high vacuum to provide 1.80 g (65% purity, 100 % yield) of the title product. The material was used in the next step without further purification.
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.63), 0.008 (0.50), 1.069 (1.93), 1.159 (16.00), 1.167 (1.51), 1.174 (1.47), 1.191 (1.38), 1.352 (10.38), 1.908 (1.65), 2.179 (2.45), 3.568 (7.52), 7.845 (0.44), 7.920 (0.55), 7.972 (0.80), 8.198 (0.57), 8.217 (0.52), 8.390 (1.22), 8.481 (0.57), 8.487 (0.57), 10.144 (0.59). Intermediate 17
4-Bromo-3-methylpyridine 1 -oxide
Figure imgf000081_0002
4-Bromo-3-methylpyridine (620 mg, 3.60 mmol) was suspended in dichloromethane (27 ml) and 3- chlorobenzenecarboperoxoic acid (1.05 g, 77 % purity, 4.69 mmol) was added in four portions over a period of 30 min at rt. After 5 h the reaction volume was reduced to 5-6 mL by evaporation under reduced pressure. After cooling down the remaining solution, precipitation occurred and the suspension was filtered and the solid was washed with 2 mL ice-cooled dichloromethane. The filtrate was then evaporated and purified by chromatography over silica gel with a gradient of dichloromethane/methanol from 100:0 to 95:5 to provide 325 mg (48 % yield) of the title product.
LC-MS (Method 6): Rt = 0.72 min; (ESIpos): m/z = 188 [M+H]+ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 2.249 (16.00), 7.626 (2.34), 7.643 (2.61), 7.970 (1.25), 7.975 (1.32), 7.987 (1.17), 7.993 (1.19), 8.282 (2.10), 8.285 (2.08).
Intermediate 18
3 - [3 -Amino-4-(trifluoromethoxy)phenyl] -7-phenylquinazolin
Figure imgf000082_0001
3-[3-Amino-4-(trifluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (250 mg, 95% purity, 594 μηιοΐ), 4,4,5, 5-tetramethyl-2-phenyl-l,3,2-dioxaborolane (169 mg, 97% purity, 801 μιηοΐ), [1,1 -bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (24.2 mg, 29.7 μιηοΐ) and potassium carbonate (246 mg, 1.78 mmol) were disolved in a mixture of N,N-dimethylformamide (520 μΐ), water (2.1 ml) and 1 ,2-dimethoxyethane (2.9 ml). An argon stream was passed through this mixture for 5 min and then it was heated to 80°C for 2h. After cooling down the mixture to rt, the whole solution was charged on a silica gel column and eluted with a gradient of cyclohexane/ethyl acetate from 100:0 to 40:60 to provide 202 mg (86 % yield) of the title product.
LC-MS (Method 6): Rt = 2.08 min; MS (ESIpos): m/z = 398 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.56), -0.008 (4.49), 0.008 (4.45), 0.146 (0.56), 2.328 (0.62), 2.367 (0.47), 2.670 (0.66), 2.710 (0.52), 5.748 (9.61), 6.694 (3.96), 6.700 (4.14), 6.715 (4.06), 6.721 (4.49), 6.928 (8.04), 6.934 (7.65), 7.278 (3.24), 7.281 (3.42), 7.299 (3.15), 7.302 (3.09), 7.461 (1.42), 7.479 (4.72), 7.498 (3.79), 7.534 (6.04), 7.554 (9.09), 7.572 (3.79), 7.843 (8.74), 7.861 (7.88), 7.864 (5.86), 7.911 (3.71), 7.916 (4.14), 7.932 (4.02), 7.936 (4.76), 7.993 (7.83), 7.997 (7.32), 8.255 (7.63), 8.276 (6.68), 8.369 (16.00).
Intermediate 19
4-bromo- 1 -(difluoromethoxy)-2-nitrobenzene
Figure imgf000082_0002
To a solution of 4-bromo-2-nitrophenol (10.0 g, 45.9 mmol) in dichloromethane (120 ml) was added a solution of potassium hydroxide (15.4 g, 275 mmol) in water (61 ml) dropwise at 0 °C, then [bromo(difluoro)methyl](trimethyl)silane (18.6 g, 91.7 mmol) was added dropwise at 0 °C. After stirring at 20 °C for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 100: 1 to 50: 1) to give the title compound (7.00 g, 66% purity, 38% yield) as a yellow oil.
'H NMR (400MHz, DMSO-d6) δ [ppm] = 8.34 (d, 1H), 8.00 (dd, 1H), 7.56-7.18 (m, 2H)
Intermediate 20
4-(difluoromethoxy)-3-nitroaniline
Figure imgf000083_0001
To a solution of 4-bromo-l-(difluoromethoxy)-2 -nitrobenzene (7.00 g, 66%> purity, 17.2 mmol) and ammonium hydroxide (24.0 ml, 170 mmol, 25%> purity in water) in 1 -methyl -2 -pyrrolidinone (30 ml) was added copper(I) oxide (123 mg, 862 μιηοΐ). After stirring at 80 °C for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 100: 1 to 50: 1) to give the title compound (2.90 g, 90%> purity, 74%> yield) as a brown solid.
LC-MS (Method 9): Rt = 0.646 min; MS (ESIpos): m/z = 205.1 [M+H]+
'H NMR (400MHz, DMSO-d6) δ [ppm] = 7.23-6.83 (m, 4H), 5.79 (s, 2H)
Intermediate 21
4-bromo-2-[(tert-butoxycarbonyl)amino]benzoic acid
Figure imgf000083_0002
To a solution of 2-amino-4-bromobenzoic acid (30.0 g, 139 mmol) and triethylamine (58.0 ml, 420 mmol) in N,N-dimethylformamide (300 ml) was added di-tert-butyl dicarbonate (48.0 ml, 210 mmol). After stirring at 50 °C for 16 hours, the mixutre was diluted with water, adjusted to pH<5 with 0.5M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 2: 1 to 1 :3) to give the title compound (26.0 g, 95% purity, 56% yield) as white solid.
'H NMR (400MHz, DMSO-d6) δ [ppm] = 10.59 (s, 1H), 8.52 (d, 1H), 7.88 (d, 1H), 7.28 (dd, 1H), 1.46 (s, 9H)
Intermediate 22
tert-butyl (5-bromo-2-{[4-(difluoromethoxy)-3-nitrophenyl]carbamoyl}phenyl)carbamate
Figure imgf000084_0001
To a solution of 4-bromo-2-((tert-butoxycarbonyl)amino)benzoic acid (5.55 g, 95% purity, 16.7 mmol), 4-(difluoromethoxy)-3-nitroaniline (2.10 g, 90% purity, 9.26 mmol), benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate (9.64 g, 18.5 mmol) in N,N-dimethylformamide (50 ml) was added N,N-diisopropylethylamine (4.80 ml, 28.0 mmol). The mixture was stirred at 40 °C for 16 hours. Another batch was prepared under similar reaction conditions (400 mg of 4- (difluoromethoxy)-3-nitroaniline, 90% purity). The two reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give the title compound (3.70 g, 90% purity) as a yellow solid.
LC-MS (Method 9): Rt = 1.041 min; MS (ESIpos): m/z = 523.9 and 525.9 [M+Na]+
¾ NMR (400MHz, DMSO-d6) δ [ppm] = 10.87 (s, 1H), 9.96 (s, 1H), 8.49 (d, 1H), 8.27 (d, 1H), 7.99 (dd, 1H), 7.76 (d, 1H), 7.55 (d, 1H), 7.49-7.10 (m, 2H), 1.44 (s, 9H)
Intermediate 23
7-bromo-3-[4-(difluoromethoxy)-3-nitrophenyl]quinazolin-4(3H)-one
Figure imgf000085_0001
A solution of tert-butyl (5-bromo-2-((4-(difluoromethoxy)-3-nitrophenyl)carbamoyl)phenyl)car-bamate (3.12 g, 90% purity, 5.59 mmol) in formic acid (30 ml) was stirred at 80 °C for 2 hours. The mixture was concentrated to give the title compound (2.10 g, 90% purity, 82% yield) as a white solid.
LC-MS (Method 9): Rt = 0.850 min; MS (ESIpos): m/z = 411.8 and 413.8 [M+H]+
1H NMR (400MHz, DMSO-d6) δ [ppm] = 8.47 (s, 1H), 8.43 (d, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 8.00 (d, 1H), 7.79 (dd, 1H), 7.75 (d, 1H), 7.48 (t, 1H)
Intermediate 24
3-[3-amino-4-(difluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one
Figure imgf000085_0002
To a solution of 7-bromo-3-(4-(difluoromethoxy)-3-nitrophenyl)quinazolin-4(3H)-one (2.10 g, 90% purity, 4.59 mmol) in tetrahydrofuran (20 ml) and water (20 ml) were added tin(II) chloride (4.14 g, 18.3 mmol) and hydrochloric acid (0.038 ml, 12 M, 0.460 mmol), the mixture was stirred at 60 °C for 16 hours. Another batch was prepared under similar reaction conditions (400 mg of 7-bromo-3-(4- (difluoromethoxy)-3-nitrophenyl)quinazolin-4(3H)-one, 90% purity). The two reaction mixtures were combined, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 5: 1 to 1 :1) to give the title compound (1.96 g, 95% purity) as a gray solid.
LC-MS (Method 9): Rt = 0.785 min; MS (ESIpos): m/z = 383.9 and 385.9 [M+H]+
'H NMR (400MHz, DMSO-d6) δ [ppm] = 8.34 (s, 1H), 8.10 (d, 1H), 7.96 (d, 1H), 7.76 (dd, 1H), 7.41 - 6.93 (m, 2H), 6.85 (d, 1H), 6.66 (dd, 1H), 5.44 (s, 2H)
Intermediate 25
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000086_0001
3-[3-amino-4-(difluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (100 mg, 262 μιηοΐ) and 1- (morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (CAS 1257236-65-9) (67.1 mg, 323 μιηοΐ) were dissolved in pyridine (5 ml). T3P (620 μΐ, 50 % purity, 1.0 mmol) was added at rt and the reaction mixture was allowed to stir at 50 °C for 2 h. The solvent was then evaporated under reduced pressure and the residue was dissolved in a mixture of acetonitrile, THF, MeOH and water. Due to poor solubility of the desired compound, a portion of it precipitated and was filtered and dried under high vacuum to afford 24 mg (83 % purity, 14 % yield) of the title compound. The remaining solution was purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% formic acid) to afford 55 mg (39 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.07 min; MS (ESIpos): m/z = 535 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.006 (2.00), 0.007 (1.27), 1.096 (2.74), 1.106 (7.34), 1.112 (7.57), 1.120 (3.44), 1.177 (0.47), 1.244 (3.53), 1.252 (7.84), 1.258 (6.50), 1.268 (2.62), 1.371 (0.60), 2.073 (0.95), 3.724 (9.54), 7.323 (3.67), 7.329 (3.62), 7.341 (5.07), 7.343 (4.53), 7.346 (4.91), 7.490 (10.18), 7.506 (4.32), 7.637 (2.88), 7.760 (4.25), 7.764 (4.25), 7.777 (4.54), 7.781 (4.64), 7.970 (7.86), 7.974 (7.46), 8.094 (8.11), 8.111 (7.20), 8.372 (16.00), 8.518 (7.76), 8.523 (7.52), 10.676 (6.48). Intermediate 26
Figure imgf000087_0001
3-[3-amino-4-(difluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (500 mg, 1.31 mmol) and l-(4- Methylpiperazin-l -yl)cyclopropanecarboxylic acid hydrochloride (WO2014147021A2, Intermediate 42) (433 mg, 1.96 mmol) were dissolved in Dioxan under Argon. Pyridine (1.0 ml) and T3P (1.2 ml, 50 % purity, 2.00 mmol) were added at rt and the reaction mixture was allowed to stir at 50 °C. After 3.5 h, analysis of the reaction mixture by HPLC showed only partial conversion oft he starting material. Pyridine (1.0 ml) was added and the reaction mixture was then allowed to stir at 105 °C for 10 h. T3P (1.0 ml, 50 % purity, 1.67 mmol) was added one more time and the reaction was allowed to stir at 105 °C overnight. The solvent was then evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient ethyl acetate/methanol from 95:5 to 80:20 to provide 760 mg (90 % purity, 95 % yield) of the title product.
LC-MS (Method 6): Rt = 1.27 min; MS (ESIpos): m/z = 548 [M+H]+
Ή-ΝΜΡν (500 MHz, DMSO-d6) δ [ppm] : -0.120 (1.13), -0.007 (16.00), 0.006 (7.85), 0.117 (1.08), 0.924 (3.31), 0.927 (3.36), 0.937 (7.39), 0.942 (5.22), 0.952 (4.46), 1.020 (0.83), 1.033 (0.73), 1.041 (0.46), 1.055 (1.18), 1.069 (0.73), 1.146 (1.45), 1.156 (3.63), 1.161 (4.95), 1.170 (2.21), 1.175 (3.17), 1.189 (1.86), 1.202 (0.54), 1.221 (2.18), 1.228 (4.28), 1.234 (3.01), 1.245 (1.18), 1.467 (2.12), 1.486 (3.68), 1.493 (2.64), 1.506 (1.72), 1.585 (1.13), 1.908 (1.72), 1.988 (5.22), 2.362 (0.75), 2.635 (1.21), 2.741 (3.09), 3.006 (0.70), 3.441 (2.74), 3.516 (3.28), 3.538 (3.09), 4.008 (0.51), 4.022 (1.32), 4.037 (1.26), 4.051 (0.48), 7.279 (1.56), 7.368 (2.10), 7.373 (1.96), 7.385 (2.66), 7.390 (2.58), 7.426 (3.23), 7.472 (3.58), 7.489 (2.47), 7.573 (1.45), 7.766 (2.72), 7.770 (2.64), 7.783 (2.85), 7.787 (2.88), 7.977 (5.08), 7.981 (4.65), 8.094 (5.03), 8.111 (4.41), 8.347 (2.53), 8.364 (10.19), 10.247 (1.05). Intermediate 27
tert-butyl (1 -carbamoylcyclopropyl)carbamate
Figure imgf000088_0001
To a solution of 1-aminocyclopropane-l -carboxamide (750 mg, 7.49 mmol) in dioxane (17 ml) was added N,N-diisopropylethylamine (1.9 ml, 11 mmol) and di-tert-butyl dicarbonate (1.9 ml, 8.2 mmol) at rt. The reaction mixture was sonicated in an ultrasound bath during 20 min and the resulting suspension was stirred at 60°C overnight. After 16 h, dioxane was evaporated under reduced pressure and 20 mL water were added. The aqueous phase was extracted with dichloromethane (x2) and with EtOAc (x2). The combined organic fractions were dried by filtration over a water-removing filter and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/MeOH from 100: 1 to 90:10 to provide the title compound 781 mg (52 % yield).
'H-NMR (500 MHz, DMSO-ifc): δ [ppm] = 7.33 (s, 1H), 7.10-6.90 (m, 2H), 1.38 (s, 9H), 1.23-1.13 (m, 2H), 0.87-0.78 (m, 2H).
Intermediate 28
tert-butyl ( 1 - { [5 -nitro-2-(trifluoromethoxy)phenyl] carbamoyl} cyclopropyl)carbamate
Figure imgf000088_0002
A suspension of tert-butyl (l-carbamoylcyclopropyl)carbamate (435 mg, 2.17 mmol), 2-bromo-4-nitro- 1 -(trifluoromethoxy)benzene (683 mg, 2.39 mmol), cesium carbonate (2.12 g, 6.52 mmol), tris(dibenzylidenacetone)dipalladium (199 mg, 217 μιηοΐ) and xantphos (251 mg, 434 μιηοΐ) in dioxane (22 ml) was degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated under argon to 80°C for 18 h. The mixture was then cooled down to rt, filtered through celite and rinsed with EtOAc. The filtrate was washed with water and brine, dried by filtration over a water- removing filter and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/EtOAc from 95:5 to 65:35 to provide the title compound 792 mg (77 % purity, 69 % yield).
LC-MS (Method 1): Rt = 1.08 min; MS (ESIneg): m/z = 404 [M-H]"
Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.088 (1.42), 1.097 (3.98), 1.104 (3.87), 1.112 (1.57), 1.398 (7.64), 1.406 (16.00), 1.424 (5.27), 1.430 (4.35), 1.440 (1.70), 7.726 (1.43), 7.729 (1.37), 7.744 (1.58), 7.747 (1.45), 7.841 (0.46), 8.083 (1.22), 8.089 (1.21), 8.102 (1.10), 8.107 (1.06), 9.035 (0.46), 9.397 (0.59).
Intermediate 29
tert-butyl (l -{[5-amino-2-(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate
Figure imgf000089_0001
To a solution of tert-butyl (l- {[5-nitro-2-(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (792 mg, 77 % purity, 1.49 mmol) in THF (6.0 ml) and ethanol (14 ml) was added the catalyst Pd/C 10% (79.2 mg) and the mixture was hydrogenated under normal pressurefor 18 h. The reaction mixture was then filtered over celite, rinsing with EtOH and THF, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with a cyclohexane/EtOAc gradient from 80:20 to 50:50. The material obtained was purified by preparative RP-HPLC 125x40mm with acetonitrile/water (0,2% Ammonia) to provide the title compound 491 mg (88 % yield).
LC-MS (Method 1): Rt = 0.91 min; MS (ESIneg): m/z = 374 [M-H]"
Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.005 (1.17), 1.014 (3.13), 1.021 (3.04), 1.029 (1.23), 1.336 (1.64), 1.344 (3.75), 1.351 (3.49), 1.360 (1.81), 1.390 (16.00), 5.374 (4.57), 6.287 (1.21), 6.292 (1.20), 6.305 (1.26), 6.310 (1.21), 7.003 (1.46), 7.006 (1.43), 7.021 (1.38), 7.023 (1.29), 7.483 (0.67), 7.858 (0.55), 8.720 (2.84). Intermediate 30
tert-butyl (l -{[5-(4-bromo-2-nitrobenzamido)-2- (trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate
Figure imgf000090_0001
A solution of tert-butyl (l -{[5-amino-2-(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (285 mg, 759 μηιοΐ), 4-bromo-2-nitrobenzoic acid (205 mg, 835 μηιοΐ) and N,N-diisopropylethylamine (400 μΐ, 2.3 mmol) in DMF (1.9 ml) was treated with HATU (577 mg, 1.52 mmol) and stirred at rt overnight. After 18 h the reaction mixture was partitioned between water and EtOAc. After phase separation, the aqueous layer was extracted (x3) wwith EtOAc. The combined organic extracts were washed with brine, dried, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/EtOAc from 90: 10 to 50:50 to provide the title product 377 mg (82 % yield).
LC-MS (Method 6): Rt = 2.16 min; MS (ESIneg): m/z = 601 [M-H]"
Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.039 (0.85), 1.048 (2.36), 1.055 (2.26), 1.063 (0.95), 1.364 (1.24), 1.372 (2.84), 1.379 (2.81), 1.388 (2.45), 1.398 (16.00), 1.403 (11.93), 7.428 (0.85), 7.430 (0.84), 7.446 (1.09), 7.561 (0.95), 7.565 (0.92), 7.578 (0.72), 7.583 (0.70), 7.745 (2.39), 7.761 (2.55), 8.093 (1.52), 8.097 (1.47), 8.109 (1.33), 8.113 (1.34), 8.370 (2.85), 8.374 (2.73), 8.500 (0.42), 9.053 (0.48), 10.895 (2.38).
Intermediate 31
tert-butyl (l-{[5-(2-amino-4-bromobenzamido)-2-
(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate
Figure imgf000091_0001
Two batches of substrate were independently hydrogneated and combined for purification. In the first batch, to a solution of tert-butyl (l- {[5-(4-bromo-2-nitrobenzamido)-2- (trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (50.0 mg, 98 % purity, 81.2 μιηοΐ) in THF (2.0 ml) and ethanol (3.0 ml) was added the catalyst (CAS 7440-06-4) platinum 1% and vanadium 2% over active charcoal (5.00 mg) and the reaction mixture was hydrogenated under atmospheric pressure for 18 h. The reaction mixture was then filtered over celite, rinsing with EtOH and THF. The filtrate was evaporated and the residue was combined with the crude material of another batched reacted similarly from 325 mg of tert-butyl (l -{[5-(4-bromo-2-nitrobenzamido)-2- (trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (528 μιηοΐ). A chromatography over silica gel was performed eluting with a gradient of cyclohexane/EtOAc from 90: 10 to 60:40 to provide the title product 282 mg (95 % purity, 77% yield).
LC-MS (Method 6): Rt = 2.20 min; MS (ESIneg): m/z = 571 [M-H]"
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.006 (0.45), 1.039 (1.08), 1.048 (2.74), 1.055 (2.57), 1.063 (1.11), 1.356 (2.76), 1.364 (1.71), 1.372 (3.50), 1.379 (3.43), 1.388 (2.85), 1.404 (16.00), 6.593 (3.08), 6.717 (1.45), 6.721 (1.35), 6.734 (1.42), 6.738 (1.35), 6.976 (2.97), 6.980 (2.67), 7.377 (1.11), 7.395 (1.34), 7.562 (1.66), 7.567 (1.65), 7.574 (2.52), 7.580 (1.47), 7.585 (1.43), 7.591 (2.20), 7.845 (0.52), 8.580 (0.55), 9.006 (0.72), 10.231 (2.77).
Intermediate 32
tert-butyl (l -{[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate
Figure imgf000092_0001
tert-butyl ,-amino-4-bromobenzamido)-2-
(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (280 mg, 95 % purity, 464 μηιοΐ) was disolved in (diethoxymethoxy)ethane (10 ml, 61 mmol) and stirred at 120°C for 2 days. The volatiles were then evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/MeOH from 100:0 to 90: 10 to provide the title product. 272 mg (99 % yield).
LC-MS (Method 6): Rt = 2.18 min; MS (ESIpos): m/z = 583 [M+H]+
Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.056 (1.15), 1.065 (3.03), 1.072 (2.89), 1.081 (1.24), 1.140 (1.33), 1.361 (1.56), 1.369 (3.62), 1.376 (3.35), 1.385 (1.93), 1.413 (16.00), 7.424 (1.10), 7.429 (1.10), 7.441 (1.24), 7.447 (1.24), 7.652 (1.38), 7.654 (1.38), 7.669 (1.19), 7.672 (1.10), 7.765 (1.79), 7.769 (1.79), 7.782 (1.97), 7.786 (2.02), 7.864 (0.46), 7.973 (3.30), 7.977 (3.16), 8.102 (3.67), 8.119 (3.26), 8.374 (0.50), 8.414 (7.52), 9.245 (0.73).
Intermediate 33
2-amino-4-bromo-3-fluoro-N-(3-nitro-4-(trifluoromethoxy)phenyl)benzamide
Figure imgf000092_0002
To a suspension of 2-amino-4-bromo-3-fluorobenzoic acid (5.00 g, 21.5 mmol) and 3-nitro-4- (trifluoromethoxy) aniline (4.50 g, 21.5 mmol) in dry THF (100 ml) was added trimethylamine (18.0 ml, 129 mmol), followed by T3P (50 % in ethyl acetate, 38.5 ml, 64.5 mmol). After stirring the reaction mixture for 8 h at 50 °C, 100 ml of 2 M HCl were added and stirring was continued over night. The cooled mixture was diluted with 100 ml ethyl acetate and the aqueous phase was extracted twice with 50 ml ethyl acetate. The combined organic solvents were washed with a saturated aqueous NaHC03 solution, and brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was triturated with little DCM, the solid filtered, washed with ether, and dried. The product was obtained as off-white solid (7.0 g, 68 % yield, 92 % purity) and used as such in the next step without further purification.
HPLC/MS (Method 10): tr = 7.42 min, [M+H]+ 438, 440; [M+H+CH3CN]+ 477, 479; [M-H]" 436, 438. Intermediate 34
7-bromo-8-fluoro-3-(3-nitro-4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one
Figure imgf000093_0001
To a solution of 2-amino-4-bromo-3-fluoro-N-(3-nitro-4-(trifluoromethoxy)phenyl)benzamide (7.00 g, 14.6 mmol) in triethylorthoformate (70.0 ml) was added TFA (700 μΐ, 8.76 mmol) and the reaction mixture was stirred at 120 °C over night. All volatiles were removed under reduced pressure and the residue was passed through a short silica gel column eluting with cyclohexane/ethyl acetate 4: 1. The product was obtained as pale yellow solid (5.50 g, 77 % yield, 80 % purity) and was used in the next step without further purification.
HPLC/MS (Method 10): tr = 6.62 min, [M+H]+ 448, 480; [M+H+CH3CN]+ 489, 491 ; [M-H]" 436, 438; [M-H+Cl]- 481, 483, [M-H+HCC ]" 491, 493.
Intermediate 35
3-(3-amino-4-(trifluoromethoxy)phenyl)-7-bromo-8-fluoroquin-azolin-4(3H)-one
Figure imgf000093_0002
To a solution of 7-bromo-8-fluoro-3-(3-nitro-4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one (5.50 g, 12.3 mmol) in acetic acid (275 ml) was added iron powder (3.40 g, 61.3 mmol) and the reaction mixture was stirred for 6 h at rt. After that time additional iron powder (1.70 g, 60.7 mmol) was added and stirring continued over night. The mixture was filtered over Celite®, washed with acetic acid, and the solvent removed under reduced pressure. The residue was taken up in a saturated aqueous NaHC03 solution and ethyl acetate and the precipitate filtered over Celite®. The aqueous phase was extracted with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 3: 1) and it was obtained as yellow solid (3.10 g, 58 % yield, 97 % purity).
HPLC/MS (Method 10): tr = 6.12 min, [M+H]+ 418, 420; [M+H+CH3CN]+ 459, 461 ; [M-H+H20]- 434, 436; [M-H+Cl]- 452, 454; [M-H+HC02]- 462, 464.
!H-NMR (CDCI3): δ = 4.3 (s, 2H), 6.7-7.1 (m, 2H), 7.3-7.5 (m, 1H), 7.6-7.9 (m, 1H), 8.0-8.2 (m, 1H), 8.3 (s, 1H). Intermediate 36
N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000094_0001
To a suspension of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-8-fluoroquinazolin-4(3H)-one (600 mg, 1.43 mmol) and l -(morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (CAS 1257236-65-9) (447 mg, 2.15 mmol) in 1,4-dioxane (15 ml) were added pyridine (350 μΐ, 4.3 mmol) and T3P (1.7 ml, 50 % purity, 2.9 mmol) was added at rt and the reaction mixture was allowed to stir at 105 °C for 22 h. The solvent was then evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate to provide 722 mg (98 % purity, 86 % yield) of the title product.
LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.112 (3.54), 1.121 (9.82), 1.127 (10.03), 1.135 (4.35), 1.175 (0.71), 1.236 (0.61), 1.270 (4.46), 1.278 (10.33), 1.284 (8.61), 1.294 (3.34), 1.356 (0.61), 1.443 (0.51), 1.760 (0.81), 1.988 (1.22), 2.363 (0.61), 2.463 (13.06), 2.472 (9.72), 2.637 (0.51), 3.601 (0.71), 3.700 (12.66), 5.752 (1.01), 7.407 (4.76), 7.412 (4.66), 7.424 (5.27), 7.430 (5.16), 7.702 (4.15), 7.705 (4.05), 7.720 (3.75), 7.852 (2.94), 7.864 (3.14), 7.869 (4.86), 7.881 (4.96), 7.919 (7.70), 7.937 (4.35), 8.461 (16.00), 8.571 (9.42), 8.576 (9.1 1), 10.619 (8.71). Intermediate 37
4-bromo- 1 -(methoxymethyl)-2-nitrobenzene
Figure imgf000095_0001
To a solution of (4-bromo-2-nitrophenyl)methanol (24.0 g, 103 mmol) and water (300 ml) in dichloromethane (300 ml) was added sodium hydroxide (29.0 g, 724 mmol) in portions, the mixture was stirred at room temperature for 15 minutes, tetra-n-butylammonium sulfate (60.1 g, 103 mmol, 50% purity in water) was added in one portion at room temperature, then dimethyl sulfate (26.1 g, 207 mmol) was added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 1 : 0 to 100: 1) to give the title compound (22.0 g, 90% purity, 78%> yield) as a yellow oil.
'H NMR (400MHZ, CDCI3) δ [ppm] = 8.23 (d, 1H), 7.77 (d, 1H), 7.69 (d, 1H), 4.79 (s, 2H), 3.50 (s, 3H) Intermediate 38
4-(methoxymethyl)-3-nitroaniline
Figure imgf000095_0002
To a solution of 4-bromo- l-(methoxymethyl)-2-nitrobenzene (22.0 g, 90%> purity, 80.5 mmol) in 1- methyl-2-pyrrolidinone (150 ml) were added ammonium hydroxide (170 ml, 1.2 mol, 25%> purity in water) in one portion and copper(I) oxide (576 mg, 4.02 mmol). After stirring at 80 °C for 16 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 10: l to 5: l) to give the title compound (8.50 g, 90% purity, 52% yield) as a yellow oil.
¾ NMR (400MHz, CDC13) δ [ppm] = 7.46 (d, 1H), 7.33 (d, 1H), 6.91 (dd, 1H), 4.70 (s, 2H), 3.93 (br s, 2H), 3.44 (s, 3H) Intermediate 39
tert-butyl (5-bromo-2-{[4-(methoxymethyl)-3-nitrophenyl]carbamoyl}phenyl)carbamate
Figure imgf000096_0001
To a solution of 4-bromo-2-((tert-butoxycarbonyl)amino)benzoic acid (22.6 g, 90% purity 64.2 mmol), 4-(methoxymethyl)-3-nitroaniline (6.50 g, 90% purity, 32.1 mmol) and benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate (33.4 g, 64.2 mmol) in N,N-dimethylformamide (80 ml) was added N,N-diisopropylethylamine (17.0 ml, 96.0 mmol), the mixture was stirred at room temperature for 16 hours. Another batch was prepared under similar reaction conditions (2.00 g of 4- (methoxymethyl)-3-nitroaniline, 90% purity).The two mixtures were combined, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (1000 mesh, petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give the title compound (11.6 g, 90% purity) as a light yellow solid.
¾ NMR (400MHz, DMSO-d6) δ [ppm] = 10.84 (s, 1H), 9.98 (s, 1H), 8.50 (d, 1H), 8.28 (d, 1H), 8.01 (dd, 1H), 7.78 (d, 1H), 7.70 (d, 1H), 7.40 (dd, 1H), 4.72 (s, 2H), 3.35 (s, 3H), 1.44 (s, 9H) Intermediate 40
7-bromo-3-[4-(methoxymethyl)-3-nitrophenyl]quinazolin-4(3H)-one
Figure imgf000097_0001
A solution of tert-butyl (5-bromo-2-((4-(methoxymethyl)-3-nitrophenyl)carbamoyl)phenyl)car-bamate (11.6 g, 90% purity, 21.7 mmol) in formic acid (100 ml) was stirred at 80 °C for 2 hours. The mixture was concentrated to give the title compound (7.50 g, 90% purity, 80%> yield) as a white solid.
¾ NMR (400MHz, DMSO-d6) δ [ppm] = 8.47 (s, 1H), 8.37 (d, 1H), 8.13 (d, 1H), 8.02-7.95 (m, 2H), 7.90 (d, 1H), 7.79 (dd, 1H), 4.84 (s, 2H), 3.41 (s, 3H) Intermediate 41
3 - [3 -amino -4 -(methoxymethyl)phenyl] -7 -bromoquinazolin-4(3 H) -one
Figure imgf000097_0002
To a mixture of 7-bromo-3-(4-(methoxymethyl)-3-nitrophenyl)quinazolin-4(3H)-one (1.95 g, 90%> purity, 4.50 mmol) and water (40 ml) in tetrahydrofuran (40 ml) was added tin(II) chloride dihydrate (4.06 g, 18.0 mmol), the mixture was stirred at 60 °C for 2.5 hours. Another batches were prepared under similar reaction conditions (1.00 g of 7-bromo-3-(4-(methoxymethyl)-3-nitrophenyl)quinazolin- 4(3H)-one , 90%> purity; 1.95 g of 7-bromo-3-(4-(methoxymethyl)-3-nitrophenyl)quinazolin-4(3H)-one, 90% purity two batches). The mixtures were combined, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chormatography on silica gel (100-200 mesh, petroleum ether: ethyl acetate = 5: 1 to 1 : 1) to give the title compound (2.80 g, 94% purity) as a white solid.
LC-MS (Method 9): Rt = 0.742 min; MS (ESIpos): m/z = 359.9 and 361.9 [M+H]+
¾ NMR (400MHz, DMSO-d6) δ [ppm] = 8.33 (s, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.76 (dd, 1H), 7.19 (d, 1H), 6.72 (d, 1H), 6.62 (dd, 1H), 5.28 (s, 2H), 4.37 (s, 2H), 3.31 (s, 3H)
Intermediate 42
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phenyl]-l -(morpholin-4-yl)cyclopropane- 1 -carboxamide
Figure imgf000098_0001
A suspension of l -(morpholin-4-yl)cyclopropane-l -carboxylic acid— hydrogen chloride (1/1) (674 mg, 3.24 mmol) in dioxane (13 ml) was treated at rt with pyridine (520 μΐ, 6.5 mmol) and T3P (1.9 ml, 50 % purity, 3.2 mmol). The reaction mixture was heated to 80°C and 3-[3-amino-4-(methoxymethyl)phenyl]- 7-bromoquinazolin-4(3H)-one (500 mg, 94 % purity, 1.30 mmol) was added. The reaction mixture was then heated at 110°C (bad temperature) for 2 hours. The reaction was then let to cool down to rt and the mixture was partitioned between EtOAc (80 mL) and a mixture of water (50 mL) and saturated NaHC03 aqueous solution (50 mL). After extractive work-up, the combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10 to provide 629 mg (92 % yield) of the title product.
LC-MS (Method 6): Rt = 1.96 min; MS (ESIpos): m/z = 513 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.073 (0.82), 1.085 (2.11), 1.093 (2.53), 1.103 (1.19), 1.203 (1.14), 1.213 (2.51), 1.220 (1.98), 1.233 (1.04), 2.440 (2.89), 3.342 (16.00), 3.568 (6.18), 3.716 (2.72), 3.728 (3.75), 3.739 (2.66), 4.655 (5.47), 7.246 (1.16), 7.252 (1.17), 7.266 (1.29), 7.271 (1.32), 7.525 (2.03), 7.545 (1.81), 7.758 (1.24), 7.763 (1.32), 7.779 (1.43), 7.784 (1.55), 7.971 (1.88), 7.976 (1.82), 8.096 (2.48), 8.117 (2.21), 8.338 (2.14), 8.343 (2.16), 8.375 (4.70), 10.722 (1.98). Intermediate 43
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phenyl]-l -(4-methylpiperazin-l- yl)cyclopropane-l -carboxamide
Figure imgf000099_0001
A suspension of l -(4-methylpiperazin-l-yl)cyclopropane-l -carboxylic acid— hydrogen chloride (1/1) (716 mg, 3.24 mmol) in dioxane (13 ml) was treated at rt with pyridine (520 μΐ, 6.5 mmol) and T3P (1.9 ml, 50 % purity, 3.2 mmol). The reaction mixture was heated to 80°C and 3-[3-amino-4- (methoxymethyl)phenyl]-7-bromoquinazolin-4(3H)-one (500 mg, 94 % purity, 1.30 mmol) was added. The reaction mixture was then heated at 110°C (bad temperature) for 2 hours. The reaction was then let to cool down to rt and the mixture was partitioned between EtOAc (80 mL) and a mixture of water (50 mL) and saturated NaHC03 aqueous solution (50 mL). After extractive work-up, the combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10 to provide 283 mg (41 % yield) of the title product.
LC-MS (Method 6): Rt = 1.25 min; MS (ESIpos): m/z = 526 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.059 (0.87), 1.072 (2.34), 1.079 (2.92), 1.089 (1.38), 1.168 (1.31), 1.178 (2.85), 1.185 (2.17), 1.198 (0.90), 2.206 (10.35), 2.436 (2.90), 2.477 (2.37), 3.373 (16.00), 4.619 (6.33), 7.240 (1.23), 7.245 (1.20), 7.259 (1.39), 7.265 (1.37), 7.518 (2.23), 7.538 (1.96), 7.757 (1.24), 7.762 (1.21), 7.779 (1.44), 7.783 (1.42), 7.970 (1.98), 7.974 (1.79), 8.094 (2.41), 8.115 (2.15), 8.329 (2.53), 8.334 (2.51), 8.374 (4.62), 10.619 (2.26).
Intermediate 44
N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin-3(4H)- yl]phenyl} - 1 -(4-methylpiperazin- 1 -yl)cyclopropane-l -carboxamide
Figure imgf000100_0001
An argon stream was passed through a mixture N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (methoxymethyl)phenyl]-l-(4-methylpiperazin-l-yl)cyclopropane-l -carboxamide (180 mg, 342 μιηοΐ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (95.5 mg, 376 μιηοΐ) and potassium acetate (101 mg, 1.03 mmol) in dioxane (3.4 ml) for 5 min. l,l -Bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethan-complex (16.8 mg, 20.5 μιηοΐ) was added to the mixture and it was stirred at 80°C under argon for 1.5 h and at rt overnight. The reaction mixture was then filtered through celite, rinsing twice the filter cake with THF. The filtrate was evaporated and dried under high vacuum to provide the title product. The material was used in the next step without further purification. Intermediate 45
methyl (2S)-2-(trifluoromethylsulfonyloxy)propanoate
Figure imgf000100_0002
To a solution of methyl (2S)-2-hydroxypropanoate (69.7 ml, 730 mmol) and triethylamine (122 ml, 877 mmol) in dichloromethane (500 ml) was added trifluoromethanesulfonic anhydride (132 ml, 803 mmo) at 0 °C under nitrogen and the mixture was stirred at 15 °C for 2 h. The reaction mixture was poured into water (800 ml) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with brine (500 ml), dried over sodium sulfate, filtered and concentrated under vacuum to deliver 188 g (quantitative) of the title compound which was used without further purification. Intermediate 46
methyl (2R)-2-morpholinopropanoate
Figure imgf000101_0001
To a solution of morpholine (30.3 ml, 344 mmol) and triethylamine (144 ml, 1.03 mol) in DMF (500 ml) was added dropwise methyl (2S)-2-(trifluoromethylsulfonyloxy)propanoate (105 g, 445 mmol) under nitrogen at 0 °C and the mixture was stirred at 15 °C for 24 h. The reaction mixture was diluted with water (2 1) and extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with brine (2 x 1 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 65.0 g (quantitative) of the title compound which was used without further purification.
Intermediate 47
2-morpholinopropanoic acid hydrochloride (enantiomer 1)
Figure imgf000101_0002
A mixture of methyl (2R)-2-morpholinopropanoate (50.0 g, 289 mmol) in aqueous hydrochloric acid 12 M (200 ml) was stirred for 24 h under nitrogen at 120 °C and the reaction mixture was concentrated under vacuum. The residue was stirred in methanol (200 ml) for 1 h, filtered and the solid was dried to deliver 15.4 g (99 % purity, 27 % yield) of the title compound which was used without further purification.
LC-MS (Method 7): Rt = 0.22 min; MS (ESIpos): m/z = 160 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.54 (d, 3H), 3.34 - 3.38 (m, 4H), 3.89 - 3.98 (m, 4H), 4.16 - 4.21 (m, 1H). Intermediate 48
methyl (2R)-2-(trifluoromethylsulfonyloxy)propanoate
Figure imgf000102_0001
To a solution of methyl (2R)-2-hydroxypropanoate (46 ml, 482 mmol) and triethylamine (80 ml, 575 mmol) in dichloromethane (250 ml) was added trifluoromethanesulfonic anhydride (90 ml, 545 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (300 ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (2 x 300 ml). The combined organic layers were washed with brine (2 x 300 ml), dried over sodium sulfate, filtered and concentrated under vacuum to deliver 119 g (90 % purity, 86 % yield) of the title compound which was used without further purification.
Ή-NMR (400 MHz, CDC13) δ [ppm]: 1.72 (d, 3H), 3.86 (s, 3H), 5.25 (q, 1H). Intermediate 49
methyl (2S)-2-morpholinopropanoate
Figure imgf000102_0002
To a solution of morpholine (20 ml, 227 mmol) and triethylamine (95 ml, 683 mmol) in DMF (100 ml) was added methyl (2R)-2-(trifluoromethylsulfonyloxy)propanoate (69.8 g, 295 mmol) under nitrogen at 0 °C and the mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (4 x 300 ml). The combined organic layers were washed with brine (2 x 400 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 33.0 g (95 % purity, 80 yield) of the title compound which was used without further purification.
Ή-NMR (400 MHz, CDC13) δ [ppm]: 1.29 (dd, 3H), 2.58 (t, 4H), 3.25 (q, 1H), 3.68 - 3.73 (m, 7H). Intermediate 50
2-morpholinopropanoic acid hydrochloride (enantiomer 2)
Figure imgf000103_0001
A mixture of methyl (2S)-2-morpholinopropanoate (33.0 g, 191 mmol) in aqueous hydrochloric acid 12 M (150 ml) was stirred at 120 °C for 1 h under nitrogen and the reaction mixture was concentrated under vacuum. The residue was stirred in isopropanol (70 ml) for 1 h, filtered and the solid was dried under vacuum. The solid was then dissolved in methanol (100 ml) and stirred for 1 h, filtered and the solid was dried to deliver 11.8 g (98.4 % purity, 31.2 % yield) of the title compound which was used without further purification.
LC-MS (Method 7): Rt = 0.24 min; MS (ESIpos): m/z = 160 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (3.44), 0.008 (2.78), 1.488 (15.86), 1.506 (16.00), 2.524 (1.00), 3.258 (2.67), 3.291 (3.21), 3.571 (0.40), 4.111 (0.82), 4.129 (2.23), 4.146 (2.19), 4.164 (0.79).
Intermediate 51
2-amino-4-bromo-5-fluoro-N-[3-nitro-4-(trifluoromethoxy)phenyl]benzamide
Figure imgf000103_0002
To a suspension of 2-amino-4-bromo-5-fluorobenzoic acid (5.00 g, 21.5 mmol) and 3-nitro-4- (trifluoromethoxy) aniline (4.50 g, 21.5 mmol) in dry THF (100 ml) was added trimethylamine (18.0 ml, 129 mmol), followed by T3P solution in ethyl acetate (38.5 ml, 50 % purity, 64.5 mmol). After stirring the reaction mixture over the weekend at 50 °C, 2 M hydrochloric acid (100 ml) was added and stirring was continued over night. The cooled mixture was diluted with ethyl acetate (100 ml) and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic solvents were washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate 4: 1) to deliver 2.50 g (92 % purity, 27 % yield) of the title compound.
HPLC/MS (Method 10): Rt = 7.23 min, MS (ESIpos): m/z = 438 [M+H]+. Intermediate 52
7-bromo-6-fluoro-3-[3-nitro-4-(trifluoromethoxy)phenyl]quinazolin-
Figure imgf000104_0001
To a solution of 2-amino-4-bromo-5-fluoro-N-(3-nitro-4-(trifluoromethoxy)phenyl)benzamide (3.96 g, 9.04 mmol) in triethylorthoformate (45.0 ml) was added trifluoroacetic acid (400 μΐ, 5.42 mmol) and the reaction mixture was stirred at 120 °C overnight. All volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (Cyclohexane/ethyl acetate 4: 1) to deliver 2.30 g (57 % yield) of the title compound.
HPLC/MS (Method 10): Rt = 6.80 min; MS (ESIpos): m/z = 448 [M+H]+. Intermediate 53
3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-6-fluoro-quinazolin-4-one
Figure imgf000104_0002
To a solution of (4.50 g, 10.0 mmol) 7-bromo-6-fluoro-3-(3-nitro-4- (trifluoromethoxy)phenyl)quinazolin-4-one in acetic acid (150 ml) was added iron powder (2.65 g, 50.0 mmol) and the reaction mixture was stirred overnight at rt. The mixture was filtered over celite, washed with acetic acid, and the solvent removed under reduced pressure. The residue was taken up in a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate and the precipitate was filtered over celite. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (Cyclohexane/ethyl acetate 3: 1) to deliver 2.20 g (52 % yield) of the title compound.
HPLC/MS (Method 10): Rt = 6.29 min; MS (ESIpos): m/z = 418 [M+H]+.
H-NMR (90 MHz, CDC13) δ [ppm] : 5.5 (s, 2H), 6.7-7.1 (m, 2H), 7.3-7.5 (m, 1H), 8.1-8.4 (m, 2H), 8.5 s, 1H). Intermediate 54
N-[5-(7-bromo-6-fluoro-4-oxoquinazolm^
yl)cyclopropane-l -carboxamide
Figure imgf000105_0001
To a suspension of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-6-fluoroquinazolin-4(3H)-one (600 mg, 1.43 mmol) and l-(morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (CAS 1257236-65-9) (447 mg, 2.15 mmol) in 1,4-dioxane (15 ml) were added pyridine (350 μΐ, 4.3 mmol) and T3P solution in ethyl acetate (1.7 ml, 50 % purity, 2.9 mmol) was added at rt and the reaction mixture was allowed to stir at 105 °C for 22 h. The solvent was then evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate to provide 558 mg (90 % purity, 62 % yield) of the title product.
LC-MS (Method 6): Rt = 2.28 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.87), -0.008 (6.86), 0.008 (5.80), 0.146 (0.73), 0.849 (1.45), 0.867 (1.06), 0.924 (2.08), 0.941 (3.77), 0.956 (2.03), 0.970 (1.16), 0.999 (0.97), 1.017 (0.97), 1.042 (0.82), 1.060 (1.11), 1.107 (3.09), 1.119 (8.02), 1.127 (9.04), 1.137 (4.45), 1.235 (2.47), 1.267 (4.21), 1.277 (9.14), 1.285 (7.88), 1.297 (3.43), 1.463 (1.60), 1.485 (2.85), 2.073 (1.11), 2.126 (0.87), 2.327 (2.61), 2.366 (1.69), 2.463 (12.04), 2.473 (10.49), 2.624 (0.63), 2.665 (2.27), 2.669 (2.66), 2.710 (1.84), 3.700 (11.17), 5.754 (4.59), 7.400 (4.54), 7.407 (4.64), 7.422 (5.17), 7.429 (5.46), 7.694 (3.72), 7.698 (3.87), 7.716 (3.34), 7.720 (3.38), 8.003 (8.41), 8.024 (8.17), 8.176 (7.78), 8.192 (7.83), 8.361 (0.48), 8.397 (16.00), 8.556 (8.75), 8.562 (8.94), 10.617 (7.54).
Intermediate 55
N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4-methylpiperazin- 1 -yl)cyclopropane-l -carboxamide
Figure imgf000106_0001
l-(4-Methylpiperazin-l-yl)cyclopropanecarboxylic acid hydrochloride (WO2014147021A2, Intermediate 42) (3.17 g, 14.3 mmol) was suspended in dichloromethane (100 ml) and 1 -chloro-N,N,2- trimethylprop-l -en-l-amine (3.83 g, 28.7 mmol) was added. This mixture was stirred at rt for 2 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (100 ml) and the mixture was once more evaporated; this operation was repeated twice. The residue was then suspended in dichloromethane (100 ml) and pyridine (2.3 ml, 29 mmol) and 3-[3-amino-4- (trifluoromethoxy)phenyl]-7-bromo-6-fluoroquinazolin-4(3H)-one (4.00 g, 9.57 mmol) were added. This reaction mixture was stirred for 18 h at rt. Dichloromethane and water were added subsequently and the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The crude material was purified by by chromatography over silica gel eluting with a gradient dichloromethane/methanol to provide 2.87 g (96 % purity, 50 % yield) of the title product.
LC-MS (Method 6): Rt = 1.42 min; MS (ESIpos): m/z = 584 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.149 (1.66), -0.008 (16.00), 0.008 (13.76), 0.146 (1.50), 1.112 (2.54), 1.120 (2.93), 1.130 (1.47), 1.237 (1.35), 1.246 (2.93), 1.254 (2.47), 2.192 (11.03), 2.327 (2.20), 2.366 (1.58), 2.454 (4.24), 2.669 (2.00), 2.710 (1.20), 7.387 (1.62), 7.393 (1.58), 7.409 (1.81), 7.415 (1.81), 7.693 (1.35), 7.711 (1.23), 8.004 (2.85), 8.025 (2.93), 8.176 (2.51), 8.192 (2.43), 8.398 (5.47), 8.606 (2.93), 8.613 (2.97), 10.654 (2.58).
Intermediate 56
N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4-methylpiperazin- 1 -yl)cyclopropane-l -carboxamide
Figure imgf000107_0001
l-(4-Methylpiperazin-l-yl)cyclopropanecarboxylic acid hydrochloride (WO2014147021A2, Intermediate 42) (3.30 g, 14.9 mmol) was suspended in dichloromethane (47 ml) and l -chloro-N,N,2- trimethylprop-l -en-l-amine (3.20 g, 23.9 mmol) was added. This mixture was stirred at rt for 2 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (47 ml) and the mixture was once more evaporated; this operation was repeated twice. The residue was then suspended in dichloromethane (47 ml) and pyridine (1.5 ml, 18 mmol) and 3-[3-amino-4- (trifluoromethoxy)phenyl]-7-bromo-8-fluoroquinazolin-4(3H)-one (2.50 g, 5.98 mmol) were added. This reaction mixture was stirred for 18 h at rt, quenched with a saturated aqueous ammonium chloride solution (50 ml) and the organic phase was separated and evaporated. The crude material was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol to provide 2.71 g (97 % purity, 77 % yield) of the title product.
LC-MS (Method 6): Rt = 1.31 min; MS (ESIpos): m/z = 584 [M+H]+
Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.003 (0.44), 1.104 (1.63), 1.114 (4.29), 1.120 (4.46), 1.128 (1.94), 1.239 (3.03), 1.247 (5.31), 1.253 (4.46), 1.263 (1.91), 2.193 (16.00), 2.362 (0.78), 2.453 (4.97), 2.635 (0.41), 3.228 (0.44), 3.265 (0.78), 3.276 (0.92), 3.334 (0.61), 3.338 (0.58), 7.393 (2.28), 7.398 (2.18), 7.410 (2.42), 7.415 (2.42), 7.695 (1.84), 7.713 (1.74), 7.850 (1.43), 7.862 (1.50), 7.868 (2.35), 7.880 (2.42), 7.919 (3.54), 7.936 (1.94), 8.461 (7.56), 8.621 (4.12), 8.626 (4.19), 10.653 (3.64).
Intermediate 57
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-2-(morpholin-4-yl)propanamide (enantiomer 1)
Figure imgf000107_0002
3-[3-amino-4-(difluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (1.00 g, 2.62 mmol) and 2- (morpholin-4-yl)propanoic acid (enantiomer 1) (458 mg, 2.88 mmol) were dissolved in pyridine (26 ml). T3P solution in ethyl acetate (4.6 ml, 50 % purity, 7.8 mmol) was added at rt and the reaction mixture was allowed to stir overnight at 50 °C. The mixture was diluted in dichloromethane and water, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0:100 to deliver 1.14 g (99 % purity, 83 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.66 min; MS (ESIpos): m/z = 524 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.188 (15.91), 1.200 (16.00), 1.234 (0.42), 2.074 (2.51), 2.386 (0.42), 2.516 (2.32), 2.564 (3.66), 2.575 (1.84), 2.583 (1.13), 2.614 (0.42), 3.359 (1.26), 3.371 (4.47), 3.383 (4.36), 3.395 (1.22), 3.679 (8.68), 7.310 (2.89), 7.340 (3.40), 7.345 (3.38), 7.355 (4.00), 7.359 (4.12), 7.432 (6.03), 7.469 (5.50), 7.483 (4.31), 7.554 (2.67), 7.766 (3.83), 7.769 (3.96), 7.780 (4.11), 7.784 (4.29), 7.976 (7.15), 7.979 (7.04), 8.102 (7.67), 8.116 (6.96), 8.382 (15.18), 8.427 (6.67), 8.431 (6.71), 10.093 (6.32).
Intermediate 58
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-2-(morpholin-4-yl)propanamide (enantiomer 2)
Figure imgf000108_0001
3-[3-amino-4-(difluoromethoxy)phenyl]-7-bromoquinazolin-4(3H)-one (1.00 g, 2.62 mmol) and 2- (morpholin-4-yl)propanoic acid (enantiomer 2) (458 mg, 2.88 mmol) were dissolved in pyridine (26 ml). T3P solution in ethyl acetate (4.6 ml, 50 % purity, 7.8 mmol) was added at rt and the reaction mixture was allowed to stir overnight at 50 °C. The mixture was diluted in dichloromethane and water, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0:100 to deliver 1.05 g (99 % purity, 77 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.66 min; MS (ESIpos): m/z = 524 [M+H] i+ Ή- MR (600 MHz, DMSO-d6) δ [ppm] : 1.175 (0.64), 1.188 (15.89), 1.200 (16.00), 1.989 (0.84), 2.075 (0.76), 2.425 (0.41), 2.563 (3.55), 2.575 (1.87), 2.582 (1.15), 3.359 (1.37), 3.371 (4.51), 3.383 (4.40), 3.395 (1.20), 3.679 (8.84), 7.310 (2.95), 7.341 (3.38), 7.345 (3.37), 7.355 (4.04), 7.359 (4.15), 7.432 (6.05), 7.469 (5.56), 7.483 (4.38), 7.554 (2.69), 7.766 (3.85), 7.769 (3.99), 7.780 (4.13), 7.784 (4.34), 7.976 (7.37), 7.979 (7.21), 8.102 (7.83), 8.116 (7.02), 8.382 (15.25), 8.427 (6.68), 8.432 (6.65), 10.094 (6.45).
Intermediate 59
N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin
yl]phenyl}-l-(morpholin-4-yl)cyclopropane-l -carboxamide
Figure imgf000109_0001
An argon stream was passed through a mixture N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (methoxymethyl)phenyl]-l-(morpholin-4-yl)cyclopropane-l -carboxamide (500 mg, 974 μηιοΐ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (272 mg, 1.07 mmol) and potassium acetate (287 mg, 2.92 mmol) in dioxane (9.8 ml) for 5 min. l,l-Bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethan-complex (47.7 mg, 58.4 μηιοΐ) was added to the mixture and it was stirred at 80°C under argon for 1.5 h and at rt overnight. The reaction mixture was then filtered through celite, rinsing three times the filter cake with THF. The filtrate was evaporated and dried under high vacuum to provide the title product. The material was used in the next step without further purification.
Intermediate 60
1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropanecarbonitrile
Figure imgf000109_0002
To a solution of 6-oxa-3-azabicyclo[3.1.1]heptane tosylate (20.0 g, 73.7 mmol) in acetic acid (100 ml) were added sodium acetate (6.80 g, 82.9 mmol) and (l -ethoxycyclopropoxy)-trimethyl-silane (38 ml, 189 mmol) at 25 °C. Trimethylsily cyanide (24 ml, 192 mmol) was then slowly added and the reaction mixture was stirred at 25 °C for 12 h. The pH of the reaction was adjusted pH9 by addition of an aqueous sodium hydroxide solution (5 M) and the mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient petroleum ether/ethyl acetate from 10: 1 to 5: 1 to deliver 8.00 g (66 % yield) of the title compound.
Ή-NMR (400 MHz, MeOD) δ [ppm] : 1.17 - 1.15 (m, 2H) 1.26 - 1.24 (m, 2H), 2.11 (d, 1H), 3.00 - 2.98 (m, 1H), 3.15 - 3.07 (m, 4H), 4.53 (d, 2H).
Intermediate 61
1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane-l -carboxamide
Figure imgf000110_0001
To a solution of l -(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropanecarbonitrile (5.00 g, 30.5 mmol) and potassium carbonate (4.20 g, 30.5 mmol) in DMSO (50 ml) was added hydrperoxide (20 ml, 30 % purity, 208 mmol) and the mixture was stirred at 25 °C for 12 h. The reaction mixture was then poured into water (250 ml) and extracted with n-butanol (5 x 100 ml). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was stirred in MTBE (20 ml) for 30 min, filtered and the filter cake was collected and dried to deliver 3.40 g (100 % purity, 61.3% yield) of the title compound which was used without further purification.
LC-MS (Method 1): Rt = 0.39 min; MS (ESIpos): m/z = 183 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.98 - 0.95 (m, 2H) 1.09 - 1.62 (m, 2H), 2.10 (d, 1H), 2.95 - 2.88 (m, 2H), 3.03 (d, 2H), 4.48 (d, 1H), 7.00 (s, 1H), 7.62 (s, 1H).
Intermediate 62
N-[5-nitro-2-(trifluoromethoxy)phenyl] - 1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane- 1 - carboxamide
Figure imgf000111_0001
A mixture of 2-bromo-4-nitro-l -(trifluoromethoxy)benzene (518 mg, 1.81 mmol), l-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l -carboxamide (300 mg, 1.65 mmol), tris(dibenzylidenacetone)dipalladium (151 mg, 165 μmol), Xantphos (191 mg, 329 μιηοΐ) and cesium carbonate (1.61 g, 4.94 mmol) was suspended in dioxane (17 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated at 80°C for 16 h. After cooling to rt, the reaction mixture was filtered through celite, the filter cake was washed with ethyl acetate and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 100:0 to 50:50 to deliver 486 mg (90 % purity, 69 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 388 [M+H]+
Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.177 (0.60), 1.299 (0.94), 1.312 (3.68), 1.318 (8.03), 1.323 (4.23), 1.334 (4.16), 1.338 (7.49), 1.344 (3.04), 1.358 (0.82), 1.398 (16.00), 1.990 (1.09), 2.274 (1.35), 2.290 (1.38), 2.919 (2.20), 2.942 (3.63), 3.000 (5.55), 3.023 (3.53), 3.038 (1.82), 3.042 (1.13), 3.051 (1.19), 3.055 (1.70), 3.068 (0.81), 4.511 (4.33), 4.523 (4.23), 7.719 (0.77), 7.722 (1.92), 7.726 (1.86), 7.729 (0.72), 7.737 (0.91), 7.741 (2.17), 7.744 (2.00), 7.747 (0.73), 8.063 (3.26), 8.069 (3.24), 8.081 (2.90), 8.087 (2.93), 9.208 (4.26), 9.214 (4.17), 10.078 (1.69).
Intermediate 63
N-[5-amino-2-(trifluoromethoxy)phenyl] - 1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane- 1 - carboxamide
Figure imgf000112_0001
N-[5-nitro-2-(trifluoromethoxy)phenyl] - 1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane- 1 - carboxamide (486 mg, 90 % purity, 1.13 mmol) was disolved in a mixture of ethanol (5.3 ml) and THF (5.3 ml), palladium on activated carbon 10% (50.0 mg) was added and the reaction mixture was hydrogenated under atmospheric pressure overnight. The reaction mixture was heated up to 40 °C and then filtered warm over celite rinsing with THF. The filtrate was evaporated under reduced pressure and the residue was dried under high vacuum to deliver 413 mg (96 % purity, 98 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.84 min; MS (ESIpos): m/z = 358 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : -0.007 (0.44), 1.043 (2.51), 1.057 (4.86), 1.071 (2.45), 1.213 (1.32), 1.227 (6.37), 1.233 (16.00), 1.236 (9.51), 1.242 (9.07), 1.246 (14.40), 1.251 (5.24), 1.266 (1.13), 1.356 (2.13), 2.232 (2.79), 2.249 (2.89), 2.879 (3.61), 2.902 (8.25), 2.931 (10.73), 2.953 (4.45), 3.004 (1.57), 3.016 (3.26), 3.021 (2.07), 3.029 (2.20), 3.033 (3.11), 3.046 (1.47), 3.415 (0.41), 3.425 (0.41), 3.429 (0.97), 3.439 (1.04), 3.443 (0.94), 3.453 (0.94), 4.328 (0.60), 4.338 (1.07), 4.349 (0.50), 4.484 (7.84), 4.496 (7.72), 5.366 (11.45), 6.282 (5.27), 6.288 (5.21), 6.300 (5.36), 6.305 (5.36), 7.006 (3.67), 7.009 (3.55), 7.023 (3.51), 7.026 (3.26), 7.540 (7.47), 7.545 (7.28), 9.611 (2.82).
Intermediate 64
4-bromo-2-nitro-N-[3 - {[1 -(6-oxa-3-azabicyclo[3.1.l]heptan-3-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]benzamide
Figure imgf000112_0002
A solution of 4-bromo-2-nitrobenzoic acid (197 mg, 800 μηιοΐ) and N,N-diisopropylethylamine (380 μΐ, 2.2 mmol) in DMF (1.0 ml) was treated with HATU (553 mg, 1.46 mmol) and stirred at rt for 15 min. To this solution was added a solution of N-[5-amino-2-(trifluoromethoxy)phenyl]-l -(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l -carboxamide (260 mg, 728 μιηοΐ) in DMF (1.0 ml) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was partitioned between water and ethyl acetate. After phase separation, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 93:7 to 40:60 to provide 318 mg (99 % purity, 82 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.08 min; MS (ESIpos): m/z = 585 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.90), 1.157 (4.35), 1.175 (8.84), 1.193 (4.59), 1.241 (1.25), 1.266 (12.77), 1.284 (12.43), 1.308 (1.12), 1.398 (1.24), 1.909 (0.80), 1.988 (16.00), 2.263 (2.99), 2.284 (3.13), 2.662 (0.47), 2.907 (3.88), 2.934 (8.60), 2.972 (10.56), 3.000 (4.52), 3.017 (1.38), 3.033 (2.89), 3.054 (2.82), 3.070 (1.26), 4.003 (1.28), 4.021 (3.83), 4.039 (3.80), 4.056 (1.29), 4.503 (7.91), 4.518 (7.81), 7.430 (2.63), 7.433 (2.72), 7.452 (3.77), 7.456 (3.62), 7.554 (4.47), 7.561 (4.45), 7.577 (3.05), 7.583 (3.17), 7.739 (7.16), 7.759 (7.88), 8.092 (4.56), 8.096 (4.70), 8.112 (3.99), 8.117 (4.20), 8.369 (8.20), 8.374 (8.09), 8.624 (6.69), 8.630 (6.64), 9.840 (4.31), 10.895 (8.02).
Intermediate 65
2-amino-4-bromo-N-[3- {[l-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l-carbonyl]amino}-4- (trifluoromethoxy)phenyl]benzamide
Figure imgf000113_0001
To a solution of 4-bromo-2-nitro-N-[3- {[l -(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l- carbonyl]amino} -4-(trifluoromethoxy)phenyl]benzamide (312 mg, 533 μιηοΐ) in THF (3.0 ml) and ethanol (7.0 ml) was added catalyst platinum 1% and vanadium 2% over active charcoal (32.8 mg; CAS 7440-06-4)) and the reaction mixture was hydrogenated under atmospheric pressure for 20 h. The reaction mixture was then filtered over celite, rinsing with ethanol. The filtrate was evaporated and the residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 93:7 to 60:40 to provide 242 mg (99 % purity, 82% yield) of the title compound. LC-MS (Method 1): Rt = 1.15 min; MS (ESIneg): m/z = 553 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.03), 0.008 (1.16), 1.157 (1.67), 1.175 (3.38), 1.193 (1.74), 1.242 (1.25), 1.260 (6.29), 1.267 (16.00), 1.282 (15.18), 1.307 (1.16), 1.398 (0.69), 1.988 (6.05), 2.263 (3.62), 2.284 (3.80), 2.327 (0.61), 2.523 (1.79), 2.670 (0.63), 2.913 (4.53), 2.940 (10.67), 2.975 (12.94), 3.003 (5.31), 3.014 (1.85), 3.030 (3.50), 3.051 (3.38), 3.067 (1.51), 4.003 (0.47), 4.021 (1.45), 4.038 (1.45), 4.056 (0.45), 4.504 (9.25), 4.519 (9.09), 6.598 (10.37), 6.714 (4.96), 6.719 (5.10), 6.735 (5.00), 6.740 (5.32), 6.975 (10.40), 6.980 (10.33), 7.380 (3.36), 7.383 (3.47), 7.402 (4.40), 7.406 (4.18), 7.552 (5.49), 7.558 (5.55), 7.575 (12.53), 7.581 (5.12), 7.596 (8.28), 8.694 (8.07), 8.700 (8.02), 9.797 (5.23), 10.232 (9.63). Intermediate 66
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(6-oxa-3- azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane-l -carboxamide
Figure imgf000114_0001
2-amino-4-bromo-N-[3- {[l-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l-carbonyl]amino}-4- (trifluoromethoxy)phenyl]benzamide (240 mg, 432 μηιοΐ) was dissolved in (diethoxymethoxy)ethane (9.5 ml, 57 mmol) and stirred at 120°C for 2 days. The volatiles were then evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 90: 10 to 0: 100 to provide 151 mg (97 % purity, 99 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.13 min; MS (ESIpos): m/z = 565 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.74), -0.008 (5.58), 0.008 (5.71), 0.146 (0.68), 1.157 (2.14), 1.175 (3.84), 1.193 (1.77), 1.239 (1.83), 1.253 (4.56), 1.261 (7.75), 1.268 (5.61), 1.302 (7.29), 1.325 (1.77), 1.398 (0.90), 1.988 (5.58), 2.283 (2.26), 2.302 (2.57), 2.327 (1.83), 2.366 (1.12), 2.670 (1.64), 2.711 (0.84), 2.926 (3.10), 2.953 (6.64), 2.995 (8.25), 3.022 (3.75), 3.046 (2.42), 3.067 (2.20), 4.021 (1.36), 4.038 (1.33), 4.518 (6.17), 4.533 (6.23), 7.412 (3.97), 7.418 (3.81), 7.434 (4.37), 7.440 (4.53), 7.660 (3.19), 7.682 (2.73), 7.765 (4.25), 7.769 (4.19), 7.786 (4.59), 7.790 (4.90), 7.978 (7.84), 7.983 (7.32), 8.099 (8.09), 8.121 (7.10), 8.411 (16.00), 8.487 (6.88), 8.493 (6.60), 9.979 (3.57). Intermediate 67
2-chloropropanamide (racemate)
Figure imgf000115_0001
To a solution of ammonia (40.0 g, 2.39 mol) in THF (500 ml) was added a solution of 2- chloropropanoyl chloride (76 ml, 787.59 mmol) in THF (500 ml) dropwise at -78 °C and the mixture was stirred for 2 h at -78 °C. The mixture was then warmed to 25 °C, diluted with water (1 1) and extracted with ethyl acetate (2 x 500 ml). The combined organic extracts were washed with brine (1 1), dried over sodium sulfate and evaporated under vacuum to deliver 70.6 g (98 % purity, 82 % yield) of the title compound which was used without further purification.
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.51 (d, 3H), 4.42 (q, 1H), 7.29 (br s, 1H), 7.62 (br s, 1H). Intermediate 68
2-(3 -oxa-7-azabicyclo[3.3.1 ]nonan-7-yl)propanamide (racemate)
Figure imgf000115_0002
A mixture of 2-chloropropanamide (1.00 g, 9.30 mmol), 3-oxa-7-azabicyclo[3.3.1]nonane (1.18 g, 9.30 mmol), sodium iodide (139 mg, 929.90 μιηοΐ) and potassium carbonate (1.93 g, 13.95 mmol) in acetonitrile (10 ml) was stirred at 85 °C for 24 h. The mixture was filtered and washed with ethanol (10 ml), the filtrate was concentrated and the residue was diluted in a mixture of ethyl acetate (10 ml) ethanol (4 ml). The mixture was filtered again and the filtrate was concentrated under vacuum. The residue was recrystallized from ethanol/petroleum ether (1 :2 v/v, 15 ml) at 70-20 °C and suspended in dichloromethane (20 ml). After filtration, the filtrate was concentrated under vacuum to give 1.20 g (99 % purity, 65% yield) of the title compound which was used without further purification.
LC-MS (Method 7): Rt = 1.04 min; MS (ESIpos): m/z = 199 [M+H]+
Ή-NMR (400 MHz, CDC13) δ [ppm] : 1.21 (d, 3H), 1.62 - 1.74 (m, 3H), 1.89 (br d, 1H), 2.66 (br d, 1H), 2.85 - 3.01 (m, 3H), 3.16 (q, 1H), 3.76 - 3.87 (m, 2H), 3.91 - 4.06 (m, 2H), 5.31 (br s, 1H), 8.51 (br s, 1H). Intermediate 69
N-[5-nitro-2-(trifluoromethoxy)phenyl] -2-(3 -oxa-7-azabicyclo[3.3.1 ]nonan-7-yl)propanamide
(racemate)
Figure imgf000116_0001
A mixture of 2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)propanamide (250 mg, 1.26 mmol), 2-bromo-4- nitro-l-(trifluoromethoxy)benzene (397 mg, 1.39 mmol), tris(dibenzylidenacetone)dipalladium (115 mg, 126 μιηοΐ), Xantphos (146 mg, 252 μιηοΐ) and cesium carbonate (1.23 g, 3.78 mmol) was suspended in dioxane (13 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated at 80°C overnight. After cooling to rt, the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water and brine and the organic layer was dried, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 100:0 to 80:20 to deliver 476.5 mg (47 % purity, 43 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.06 min; MS (ESIpos): m/z = 404 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.79), 0.007 (1.26), 1.174 (15.96), 1.188 (16.00), 1.398 (13.51), 1.604 (1.33), 1.625 (2.77), 1.678 (2.17), 1.715 (2.19), 1.817 (1.59), 1.841 (1.26), 1.997 (1.43), 2.623 (1.69), 2.640 (1.55), 2.645 (2.27), 2.758 (2.07), 2.780 (1.47), 2.869 (1.67), 2.886 (1.53), 2.890 (2.41), 2.971 (2.13), 2.993 (1.39), 3.422 (1.18), 3.436 (4.00), 3.450 (3.93), 3.464 (1.10), 3.669 (1.04), 3.673 (1.79), 3.678 (1.02), 3.691 (1.77), 3.696 (2.87), 3.700 (1.53), 3.720 (1.22), 3.724 (2.07), 3.729 (1.20), 3.742 (1.67), 3.747 (2.73), 3.758 (2.83), 3.780 (1.63), 3.896 (2.45), 3.918 (1.87), 6.386 (0.72), 6.397 (0.80), 6.411 (0.74), 6.880 (0.52), 6.895 (1.06), 6.910 (0.64), 6.966 (0.44), 6.981 (0.58), 7.176 (0.42), 7.321 (0.58), 7.336 (0.96), 7.352 (0.48), 7.547 (0.50), 7.562 (1.12), 7.577 (0.74), 7.619 (0.48), 7.633 (0.58), 7.684 (1.10), 7.688 (2.65), 7.691 (2.55), 7.694 (0.98), 7.702 (1.28), 7.706 (2.97), 7.709 (2.71), 7.861 (0.66), 7.875 (0.64), 8.067 (4.56), 8.072 (4.52), 8.085 (4.08), 8.091 (4.12), 8.163 (0.82), 8.176 (0.76), 9.052 (7.03), 9.058 (6.83), 10.649 (3.29). Intermediate 70
N-[5-amino-2-(trifluoromethoxy)phenyl] -2-(3 -oxa-7-azabicyclo[3.3.1 ]nonan-7-yl)propanamide
(racemate)
Figure imgf000117_0001
N-[5-nitro-2-(trifluoromethoxy)phenyl] -2-(3 -oxa-7-azabicyclo[3.3.1 ]nonan-7-yl)propanamide (477 mg, 47 % purity, 552 μιηοΐ) was suspended in a mixture of ethanol (12 ml) and THF (3.0 ml). Palladium on activated carbon 10% (47.7 mg) was added and the reaction mixture was hydrogenated under atmospheric pressure overnight. The reaction mixture was filtered over celite rinsing with ethanol and THF. The filtrate was evaporated under reduced pressure and the residue was submitted to preparative RP-HPLC 125x40mm with acetonitrile/water (neutral conditions) to deliver 145.3 mg (99 % purity, 71 % yield) of the title compound.
LC-MS (Method 6): Rt = 0.83 min; MS (ESIpos): m/z = 374 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.135 (15.91), 1.150 (16.00), 1.235 (0.67), 1.595 (1.69), 1.618 (2.04), 1.696 (5.33), 1.803 (2.22), 1.828 (1.78), 2.072 (3.91), 2.604 (2.13), 2.626 (2.71), 2.758 (2.76), 2.780 (2.09), 2.816 (1.87), 2.838 (3.11), 2.895 (3.02), 2.917 (1.82), 3.200 (1.24), 3.214 (4.04), 3.229 (3.87), 3.243 (1.20), 3.667 (2.44), 3.690 (4.98), 3.694 (4.40), 3.717 (3.42), 3.768 (3.42), 3.790 (2.27), 3.838 (3.38), 3.860 (2.44), 5.308 (8.67), 6.325 (4.22), 6.331 (4.22), 6.343 (4.36), 6.348 (4.36), 6.961 (3.73), 6.963 (3.64), 6.978 (3.56), 6.980 (3.33), 7.125 (7.64), 7.130 (7.38), 10.054 (5.91).
Intermediate 71
4-bromo-2-nitro-N-[3- {[2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)propanoyl]amino}-4- (trifluoromethoxy)phenyl] benzamide (racemate)
Figure imgf000118_0001
A solution of 4-bromo-2-nitrobenzoic acid (210 μΐ, 2.0 M, 420 μηιοΐ) and N,N-diisopropylethylamine (200 μΐ, 1.2 mmol) in DMF (1.0 ml) was treated with HATU (293 mg, 771 μιηοΐ) and stirred at rt for 10 min. To this solution was added N-[5-amino-2-(trifluoromethoxy)phenyl]-2-(3-oxa-7- azabicyclo[3.3.1]nonan-7-yl)propanamide (144 mg, 386 μιηοΐ) and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted in acetonitrile and directly submitted to preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid). The residue was dissolved in dichloromethane and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried. Filtered and evaporated to dryness to deliver 127 mg (99 % purity, 55 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.05 min; MS (ESIneg): m/z = 599 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (1.73), 1.155 (12.08), 1.172 (12.21), 1.603 (2.41), 1.634 (3.02), 1.705 (6.65), 1.816 (3.44), 1.847 (2.76), 2.328 (1.29), 2.366 (1.22), 2.523 (4.88), 2.627 (2.47), 2.651 (3.28), 2.710 (1.35), 2.767 (3.37), 2.793 (2.57), 2.849 (2.25), 2.877 (3.69), 2.939 (3.73), 2.964 (2.35), 3.336 (3.66), 3.682 (3.34), 3.711 (7.84), 3.744 (6.20), 3.784 (3.98), 3.812 (2.54), 3.877 (4.18), 3.904 (3.15), 7.389 (3.86), 7.410 (5.01), 7.547 (8.48), 7.553 (8.29), 7.569 (6.30), 7.576 (6.27), 7.745 (14.55), 7.765 (16.00), 8.097 (8.61), 8.102 (8.77), 8.118 (7.58), 8.122 (7.90), 8.312 (12.24), 8.319 (11.69), 8.373 (13.43), 8.378 (13.08), 10.376 (8.61), 10.890 (8.61).
Intermediate 72
2-amino-4-bromo-N-[3- {[2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)propanoyl]amino}-4- (trifluoromethoxy)phenyl] benzamide (racemate)
Figure imgf000119_0001
4-bromo-2-nitro-N-[3- {[2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)propanoyl]amino}-4- (trifluoromethoxy)phenyl]benzamide (132 mg, 219 μηιοΐ) was dissolved in tetrahydrofuran (10.0 ml) and cooled to 0-5°C. Titanium(III) trichloride solution in 2N aqueous hydrochloric acid (1.4 ml, 20 % purity, 2.2 mmol) was added under stirring while keeping the temperature below 10°C. After completing the addition the mixture was stirred at 40 °C for 2 h, when full conversion was observed. After cooling down to rt, ethyl acetate (50 ml) was added and under cooling (0°C) and strong stirring the reaction mixture was neutralized by addition of solid sodium carbonate. The mixture was stirred for further 10 min and then the supernatant was decanted and filtered through a short pad of celite. The remaining material (solids) was stirred with ethyl acetate (30 ml) for 30 min and then decanted and filtered analogously. The two organic fractions were then combined, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 97:3 to 80:20 followed by a preparative RP-HPLC 220x50mm with acetonitrile/water (0.1% formic acid) to deliver 67.0 mg (97 % purity, 53 % yield) of the title compound. LC-MS (Method 6): Rt = 1.42 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.50), -0.008 (5.04), 0.008 (4.06), 0.146 (0.49), 1.158 (15.75), 1.176 (16.00), 1.235 (0.84), 1.605 (1.61), 1.636 (2.04), 1.709 (4.78), 1.818 (2.15), 1.848 (1.67), 2.073 (2.28), 2.635 (1.98), 2.662 (2.95), 2.710 (0.45), 2.765 (2.91), 2.791 (1.95), 2.861 (1.73), 2.888 (3.27), 2.940 (3.18), 2.967 (1.67), 3.296 (1.50), 3.331 (4.19), 3.348 (1.24), 3.683 (2.07), 3.711 (4.59), 3.716 (4.08), 3.745 (3.23), 3.783 (3.53), 3.811 (2.13), 3.876 (3.31), 3.904 (2.39), 6.588 (8.29), 6.718 (3.65), 6.723 (3.71), 6.739 (3.79), 6.744 (3.87), 6.977 (8.00), 6.982 (7.67), 7.339 (2.78), 7.359 (3.48), 7.565 (4.38), 7.572 (9.90), 7.587 (3.86), 7.594 (9.70), 8.339 (6.80), 8.346 (6.59), 10.213 (7.38), 10.337 (6.98).
Intermediate 73
N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(3-oxa-7- azabicyclo [3.3.1 ]nonan-7-yl)propanamide (racemate)
Figure imgf000120_0001
2-amino-4-bromo-N-[3- {[2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)propanoyl]amino}-4- (trifluoromethoxy)phenyl]benzamide (67.0 mg, 117 μηιοΐ) was dissolved in (diethoxymethoxy) ethane (2.6 ml, 16 mmol) and stirred at 120°C overnight. The volatiles were then evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 90: 10 to 50:50 to provide 27.8 mg (89 % purity, 36 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.03 min; MS (ESIpos): m/z = 582 [M+H]+ Intermediate 74
benzyl 2-(l,4-oxazepan-4-yl)propanoate (racemate)
Figure imgf000120_0002
A mixture of benzyl 2-chloropropanoate (50.0 g, 252 mmol), 1,4-oxazepane hydrochloride (34.6 g, 252 mmol), tripotassium phosphate (160 g, 755 mmol) and potassium iodide (4.18 g, 25.2 mmol) in DMF (250 ml) was stirred at 80°C for 2 h under nitrogen atmosphere. The reaction mixture was quenched by addition water (600 ml) and extracted with ethyl acetate (3 x 500 ml). The combined organic layers were washed with brine (500 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient petroleum ether/ethyl acetate from 100: 1 to 40: 1 to provide 43.0 g (92 % purity, 60 % yield) of the title product.
LC-MS (Method 11): Rt = 0.45 min; MS (ESIpos): m/z = 264 [M+H] + Ή- MR (400 MHz, CDC13) δ [ppm] : δ ppm 1.32-1.34 (m, 3H) 1.82-1.87 (m, 2H), 2.76-2.79 (m, 2 2.87-2.91 (m, 2H), 3.53-3.55 (m, 1H), 3.65-3.70 (m, 2H), 3.77-3.80 (m, 2H), 5.12-5.22 (m, 2H), 7. 7.40 (m, 5H).
Intermediate 75
benzyl 2-(l ,4-oxazepan-4-yl)propanoate (enantiomer 1)
Figure imgf000121_0001
Enantiomer separation of 43.0 g of benzyl 2-(l ,4-oxazepan-4-yl)propanoate (racemate) gave 16.4 g of enantiomer 2 (chiral SFC: Rt = 2.05 min) and 18.0 g of the title compound (enantiomer 1): chiral SFC: Rt = 1.89 min; 96.4% ee.
Method information: column: Chiralpak AY, 3 μιη 150 mm x 4.6 mm ID.; mobile phase: gradient carbon dioxide/ethanol (0.05% diethylamine in the ethanol phase) from 5% to 40%> of ethanol and hold 40%) for 2.5 min, then 5% of ethanol for 2.5 min; temperature: 35°C; flow rate: 2.5 ml/min.
Ή-NMR (400 MHz, CDC13) δ [ppm] : 1.33-1.35 (m, 3H) 1.80-1.89 (m, 2H), 2.78-2.88 (m, 2H), 2.89- 2.91 (m, 2H), 3.54-3.80 (m, 5H), 5.12-5.19 (m, 2H), 7.32-7.40 (m, 5H).
Intermediate 76
benzyl 2-(l ,4-oxazepan-4-yl)propanoate (enantiomer 2)
Figure imgf000121_0002
Enantiomer separation of 43.0 g of benzyl 2-(l ,4-oxazepan-4-yl)propanoate (racemate) gave 18.0 g of enantiomer 1 (chiral SFC: Rt = 1.89 min) and 16.4 g of the title compound (enantiomer 2): chiral SFC:
Figure imgf000121_0003
Method information: column: Chiralpak AY, 3 μιη 150 mm x 4.6 mm ID.; mobile phase: gradient carbon dioxide/ethanol (0.05%> diethylamine in the ethanol phase) from 5% to 40%> of ethanol and hold 40%) for 2.5 min, then 5% of ethanol for 2.5 min; temperature: 35°C; flow rate: 2.5 ml/min.
LC-MS (Method 12): Rt = 0.70 min; MS (ESIpos): m/z = 264 [M+H]+ Ή- MR (400 MHz, CDC13) δ [ppm]: 1.33-1.35 (m, 3H), 1.80-1.89 (m, 2H), 2.78-2.88 (m, 2H), 2. 2.91 (m, 2H), 3.54-3.80 (m, 5H), 5.12-5.19 (m, 2H), 7.32-7.39 (m, 5H).
Intermediate 77
2-(l,4-oxazepan-4-yl)propanoic acid (enantiomer 1)
Figure imgf000122_0001
To a solution of benzyl 2-(l,4-oxazepan-4-yl)propanoate (enantiomer 1) (17.5 g, 66.5 mmol) in methanol (80 ml) was added palladium on activated carbon 10% (5.00 g) and the mixture was stirred at 25°C under hydrogen pressure (15 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 8.76 g (76.1 % yield) of the title compound which was used without further purification.
Ή-NMR (400 MHz, D20) δ [ppm] : 1.48-1.50 (m, 3H), 2.15 (s, 2H), 3.46 (s, 4H), 3.85-3.97 (m, 5H).
Intermediate 78
2-(l ,4-oxazepan-4-yl)propanoic acid (enantiomer 2)
Figure imgf000122_0002
To a solution of benzyl 2-(l,4-oxazepan-4-yl)propanoate (enantiomer 2) (16.4 g, 62.4 mmol) in methanol (50 ml) was added palladium on activated carbon 10% (5.00 g) and the mixture was stirred at 25°C under hydrogen pressure (15 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 10.2 g (93.9 % yield) of the title compound which was used without further purification.
Ή-NMR (400 MHz, D20) δ [ppm] : 1.49-1.50 (m, 3H), 2.17 (s, 2H), 3.47 (s, 4H), 3.85-3.97 (m, 5H). Intermediate 79
N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4-oxazepan-4- yl)propanamide (enantiomer 1)
Figure imgf000123_0001
To a solution of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-8-fluoroquinazolin-4(3H)-one (1.20 g, 2.87 mmol) and 2-(l,4-oxazepan-4-yl)propanoic acid (enantiomer 1) (547 mg, 3.16 mmol) in dry pyridine (30 ml) was added a T3P solution in ethyl acetate (5.0 ml, 50 % purity, 8.60 mmol) and the reaction mixture was stirred overnight at 50 °C. After cooling down to rt, the mixture was evaporated and directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 85: 15 to deliver 1.45 g (99 % purity, 88 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.54 min; MS (ESIpos): m/z = 573 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.64), 0.008 (0.77), 1.157 (0.64), 1.175 (1.79), 1.185 (15.65), 1.193 (2.51), 1.202 (16.00), 1.833 (0.99), 1.848 (2.83), 1.862 (4.00), 1.877 (3.23), 1.892 (1.18), 1.988 (2.05), 2.328 (0.64), 2.366 (0.56), 2.523 (2.56), 2.670 (0.77), 2.674 (0.59), 2.701 (0.94), 2.713 (3.10), 2.734 (8.33), 2.747 (7.29), 2.758 (2.40), 2.781 (0.90), 3.647 (4.48), 3.659 (8.79), 3.670 (5.05), 3.674 (5.80), 3.692 (4.33), 3.709 (1.23), 3.729 (5.82), 3.744 (11.25), 3.759 (5.69), 4.021 (0.48), 4.038 (0.51), 7.412 (3.76), 7.419 (3.77), 7.434 (4.24), 7.440 (4.38), 7.669 (3.10), 7.672 (3.21), 7.690 (2.75), 7.694 (2.61), 7.852 (2.40), 7.867 (2.24), 7.874 (4.19), 7.888 (4.46), 7.925 (5.66), 7.927 (5.72), 7.946 (2.83), 7.949 (3.10), 8.461 (6.55), 8.467 (6.79), 8.474 (12.15), 10.088 (6.15).
Intermediate 80
N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4-oxazepan-4- yl)propanamide (enantiomer 2)
Figure imgf000123_0002
To a solution of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-8-fluoroquinazolin-4(3H)-one (1.20 g, 2.87 mmol) and 2-(l,4-oxazepan-4-yl)propanoic acid (enantiomer 2) (547 mg, 3.16 mmol) in dry pyridine (30 ml) was added a T3P solution in ethyl acetate (5.0 ml, 50 % purity, 8.60 mmol) and the reaction mixture was stirred overnight at 50 °C. After cooling down to rt, the mixture was evaporated and directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 85: 15 to deliver 1.57 g (95 % purity, 91 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.54 min; MS (ESIpos): m/z = 573 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.47), 0.008 (0.56), 1.184 (15.66), 1.202 (16.00), 1.235 (0.63), 1.833 (0.99), 1.848 (2.83), 1.862 (3.99), 1.877 (3.23), 1.892 (1.20), 2.328 (0.52), 2.366 (0.50), 2.523 (2.15), 2.665 (0.47), 2.670 (0.63), 2.674 (0.50), 2.679 (0.42), 2.700 (0.95), 2.713 (3.10), 2.724 (4.80), 2.734 (8.36), 2.747 (7.34), 2.758 (2.43), 2.781 (0.87), 2.792 (0.42), 3.647 (4.48), 3.659 (8.81), 3.670 (5.10), 3.674 (5.82), 3.692 (4.34), 3.709 (1.23), 3.729 (5.84), 3.744 (11.32), 3.759 (5.74), 5.754 (1.30), 7.412 (3.64), 7.419 (3.71), 7.434 (4.19), 7.441 (4.34), 7.669 (3.03), 7.672 (3.14), 7.690 (2.71), 7.694 (2.55), 7.852 (2.28), 7.867 (2.16), 7.873 (4.06), 7.888 (4.34), 7.925 (5.45), 7.927 (5.49), 7.949 (3.06), 8.461 (6.30), 8.467 (6.59), 8.474 (11.70), 10.089 (6.16). Intermediate 81
N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (enantiomer 1)
Figure imgf000124_0001
To a solution of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-8-fluoroquinazolin-4(3H)-one (1.00 g, 2.39 mmol) and 2-(morpholin-4-yl)propanoic acid (enantiomer 1) (419 mg, 2.63 mmol) in dry pyridine (25 ml) was added a T3P solution in ethyl acetate (4.2 ml, 50 % purity, 7.20 mmol) and the reaction mixture was stirred overnight at 50 °C. The cooled mixture was partitioned between dichloromethane and water, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to deliver 910 mg (99 % purity, 68 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.85 min; MS (ESIpos): m/z = 561 [M+H] i+ Ή- MR (600 MHz, DMSO-d6) δ [ppm] : 1.175 (0.47), 1.194 (5.10), 1.206 (5.12), 1.989 (0.88), 2.502 (16.00), 2.562 (1.93), 2.570 (1.34), 2.582 (0.67), 2.589 (0.44), 3.358 (0.82), 3.385 (0.47), 3.396 (1.38), 3.408 (1.31), 3.420 (0.41), 3.652 (2.85), 7.385 (0.46), 7.395 (0.44), 7.429 (1.03), 7.433 (1.06), 7.444 (1.15), 7.448 (1.17), 7.679 (1.11), 7.694 (0.97), 7.859 (0.71), 7.869 (0.74), 7.873 (1.11), 7.884 (1.12), 7.928 (1.94), 7.942 (1.23), 8.422 (1.96), 8.426 (1.96), 8.472 (3.90), 8.571 (0.55), 8.578 (0.53), 10.096 (2.19).
Intermediate 82
N-[5-(7-bromo-8-fluoro-4-oxoquinazolm^
yl)propanamide (enantiomer 2)
Figure imgf000125_0001
To a solution of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-8-fluoroquinazolin-4(3H)-one (1.00 g, 2.39 mmol) and 2-(morpholin-4-yl)propanoic acid (enantiomer 2) (419 mg, 2.63 mmol) in dry pyridine (25 ml) was added a T3P solution in ethyl acetate (4.2 ml, 50 % purity, 7.20 mmol) and the reaction mixture was stirred overnight at 50 °C. The cooled mixture was partitioned between dichloromethane and water, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to deliver 1.08 g (99 % purity, 80 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.85 min; MS (ESIpos): m/z = 561 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.175 (0.49), 1.194 (5.57), 1.206 (5.59), 1.989 (0.83), 2.502 (16.00), 2.562 (2.09), 2.569 (1.30), 2.581 (0.77), 2.588 (0.47), 3.299 (0.68), 3.359 (1.39), 3.384 (0.53), 3.396 (1.52), 3.408 (1.47), 3.420 (0.45), 3.652 (3.18), 7.373 (0.47), 7.382 (0.51), 7.386 (0.53), 7.395 (0.49), 7.429 (1.17), 7.433 (1.17), 7.444 (1.28), 7.448 (1.30), 7.679 (1.22), 7.694 (1.07), 7.859 (0.79), 7.869 (0.83), 7.873 (1.22), 7.883 (1.22), 7.928 (2.11), 7.942 (1.36), 8.423 (2.15), 8.426 (2.15), 8.471 (4.22), 8.571 (0.64), 8.578 (0.64), 10.096 (2.43). Intermediate 83
benzyl 2-chloropropanoate (racemate)
Figure imgf000126_0001
To a solution of benzyl alcohol (123 ml, 1.18 mol) and pyridine (95.4 ml, 1.18 mol) in dichloromethane (750 ml) was added 2-chloropropanoyl chloride (114 ml, 1.18 mol) dropwise at 0°C. The mixture was stirred at rt for 2 h until complete consumption of the starting material. The reaction mixture was then filtered and the filtrate was poured into an aqueous solution of hydrochloric acid 0.2 M (300 ml). The organic layer was washed with brine (2 x 400 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient petroleum ether/ethyl acetate to afford 190 g (95 % purity, 81 % yield) of the title compound.
H-NMR (400 MHz, CDC13) δ [ppm]: δ ppm 1.72 (d, 3H), 4.45 (q, 1H), 5.23 (s, 2H), 7.33 - 7.44 (m, 5H).
Working examples: Example 1
N-{5-[7-(5-Fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (racemate)
Figure imgf000126_0002
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (400 mg, 60% purity, 408 μιηοΐ), 3-bromo-5-fluoropyridine (96.9 mg, 551 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (16.7 mg, 20.4 μιηοΐ) and potassium carbonate (113 mg, 816 μηιοΐ) in Ν,Ν-dimethylformamide (360 μΐ), water (1.4 ml) and 1,2-dimethoxyethane (2.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 89: 11. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 165 mg (71 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.66 min; MS (ESIpos): m/z = 558 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (4.31), 0.008 (4.75), 0.146 (0.50), 1.198 (15.77), 1.216 (16.00), 2.328 (0.78), 2.567 (7.62), 2.579 (4.31), 2.597 (1.67), 2.608 (0.96), 2.670 (0.84), 3.385 (1.39), 3.402 (4.50), 3.420 (4.38), 3.437 (1.16), 3.659 (11.73), 3.669 (6.66), 7.449 (3.56), 7.455 (3.56), 7.471 (4.15), 7.477 (4.25), 7.676 (3.33), 7.679 (3.47), 7.698 (2.83), 7.701 (2.67), 8.035 (3.51), 8.040 (3.70), 8.056 (4.04), 8.060 (4.36), 8.200 (7.26), 8.204 (7.05), 8.292 (7.28), 8.298 (2.47), 8.304 (3.29), 8.313 (6.62), 8.324 (2.15), 8.329 (2.97), 8.335 (2.17), 8.429 (6.76), 8.435 (6.76), 8.446 (14.93), 8.686 (6.48), 8.693 (6.25), 8.994 (7.19), 10.099 (6.73). Example 2
N-{5-[7-(5-Fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (enantiomer 1)
Figure imgf000127_0001
Enantiomer separation of 160 mg of N-{5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(morpholin-4-yl)propanamide (racemate) gave 60 mg of enantiomer 2 (chiral HPLC: Rt = 13.5 min) and 57 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 10.5 min; 100% ee.
Separating method: column: Daicel Chiralcel OD-H, 5 μηι 250 mm x 20 mm; mobile phase: n-heptane 50%o/ethanol 50%> with 0.2%> diethylamine in the ethanol phase; temperature: 40°C; flow rate: 25 ml/min; UV detection: 210 nm.
Analysis: column: Daicel Chiralpak IB-3 3 μηι, 50 mm x 4.6 mm; mobile phase: n-heptane 50%>/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 220 nm. LC-MS (Method 6): Rt = 1.66 min; MS (ESIpos): m/z = 558 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.199 (1.22), 1.216 (1.24), 2.567 (0.60), 3.321 (14.95), 3.326 (14.70), 3.332 (16.00), 3.648 (0.53), 3.659 (0.93), 3.670 (0.53), 8.198 (0.57), 8.202 (0.53), 8.292 (0.61), 8.313 (0.52), 8.429 (0.47), 8.435 (0.46), 8.445 (1.14), 10.100 (0.52). Example 3
N-{5-[7-(5-Fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(mo^holin- 4-yl)propanamide (enantiomer 2)
Figure imgf000128_0001
Enantiomer separation of 160 mg of N-{5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(morpholin-4-yl)propanamide (racemate) gave 57 mg of enantiomer 1 (chiral HPLC: Rt = 10.5 min) and 60 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 13.5 min; 100% ee.
Separating method: column: Daicel Chiralcel OD-H, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 50%/ethanol 50% with 0.2%> diethylamine in the ethanol phase; temperature: 40°C; flow rate: 25 ml/min; UV detection: 210 nm.
Analysis: column: Daicel Chiralpak IB-3 3 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%>/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 220 nm.
LC-MS (Method 6): Rt = 1.65 min; MS (ESIpos): m/z = 558 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.86), 0.146 (0.92), 1.140 (0.65), 1.158 (1.39), 1.177 (0.85), 1.199 (15.62), 1.216 (16.00), 1.234 (1.67), 2.328 (0.79), 2.567 (8.44), 2.578 (4.75), 2.597 (1.91), 2.670 (1.01), 2.710 (0.50), 3.385 (1.37), 3.402 (4.34), 3.420 (4.23), 3.437 (1.30), 3.659 (12.67), 7.449 (3.22), 7.455 (3.38), 7.471 (3.89), 7.477 (4.07), 7.679 (3.71), 7.700 (2.93), 8.039 (3.69), 8.060 (4.39), 8.203 (7.54), 8.292 (6.57), 8.304 (3.38), 8.312 (6.52), 8.329 (3.04), 8.429 (6.80), 8.435 (7.02), 8.445 (13.71), 8.688 (4.72), 8.693 (4.75), 8.995 (5.44), 10.099 (7.04). Example 4
N-{5-[7-(5-methylpyridin-3-yl)-4-oxoquinazolin-3(4H^
4-yl)propanamide (racemate)
Figure imgf000129_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (racemate) (85.0 mg, 157 μηιοΐ), (5-methylpyridin-3-yl)boronic acid (38.7 mg, 283 μηιοΐ), bis(triphenylphosphine)palladium(II)chloride (11.0 mg, 15.7 μηιοΐ) and cesium carbonate (102 mg, 314 μηιοΐ) in N,N-dimethylformamide (1.6 ml) and water (810 μΐ) was degassed by passing argon through it for 10 min and then the mixture was heated at 100°C for 16 h. The reaction mixture was then filtered through a syringe filter and submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver a material that was then subjected to a second purification as follows. Instrument: Waters Prep LC/MS System; column: XBridge CI 8 5μηι 100x30 mm; mobile phase: water/acetonitrile plus 5 ml of 2% ammonia in water (eluent B); flow: 65 ml/min, room temperature, detection wavelength 200-400 nm. Gradient profile: 0 to 2 min 30% eluent B, 2 to 2.2 min to 50% eluent B, 2.2 to 7 min to 90% eluent B, 7 to 7.5 min to 92% eluent B, 7.5 to 9 min at 92% B. This purification yielded 12.2 mg (97 % purity, 14 % yield) of the title product.
LC-MS (Method 6): Rt = 1.51 min; MS (ESIneg): m/z = 552 [M-H]"
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : -0.007 (3.40), 0.006 (2.13), 1.200 (9.61), 1.214 (9.49), 2.362 (0.50), 2.406 (0.92), 2.421 (16.00), 2.515 (1.92), 2.519 (1.83), 2.522 (1.58), 2.559 (3.47), 2.569 (3.41), 2.578 (2.18), 2.592 (1.02), 2.601 (0.63), 2.635 (0.52), 3.389 (0.84), 3.403 (2.75), 3.417 (2.65), 3.431 (0.71), 3.658 (5.32), 7.449 (2.42), 7.454 (2.37), 7.467 (2.57), 7.472 (2.62), 7.675 (1.90), 7.678 (1.93), 7.693 (1.79), 7.696 (1.54), 7.977 (2.30), 7.980 (2.33), 7.993 (2.40), 7.997 (2.55), 8.101 (4.38), 8.104 (4.12), 8.123 (3.04), 8.284 (4.26), 8.300 (3.72), 8.425 (4.50), 8.430 (13.83), 8.514 (3.22), 8.517 (3.05), 8.871 (3.31), 8.875 (3.19), 10.097 (3.67). Example 5
2-(Morpholin-4-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin- (trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000130_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 70% purity, 119 μηιοΐ), 3-bromopyridine (16 μΐ, 98% purity, 160 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.86 mg, 5.95 μηιοΐ) and potassium carbonate (32.9 mg, 238 μηιοΐ) in N,N-dimethylformamide (100 μΐ), water (420 μΐ) and 1,2-dimethoxyethane (580 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 58.4 mg (97 % purity, 88 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.58 min; MS (ESIneg): m/z = 538 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.199 (15.08), 1.216 (15.35), 2.329 (0.68), 2.367 (0.50), 2.597 (1.96), 2.670 (0.83), 2.710 (0.53), 3.384 (1.48), 3.402 (4.30), 3.420 (4.24), 3.437 (1.33), 3.659 (12.86), 7.448 (3.38), 7.454 (3.35), 7.470 (3.97), 7.476 (4.09), 7.558 (3.02), 7.571 (3.20), 7.579 (3.17), 7.591 (3.05), 7.678 (3.73), 7.697 (2.90), 7.988 (3.44), 7.992 (3.73), 8.009 (3.88), 8.013 (4.27), 8.119 (7.29), 8.123 (7.26), 8.281 (3.59), 8.285 (3.11), 8.292 (7.44), 8.301 (3.70), 8.313 (5.87), 8.427 (6.79), 8.436 (16.00), 8.669 (3.85), 8.673 (4.15), 8.681 (3.97), 8.685 (3.97), 9.078 (5.96), 9.084 (5.96), 10.100 (6.90).
Example 6
2-(Morpholin-4-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (enantiomer 1)
Figure imgf000131_0001
Enantiomer separation of 93.5 mg of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)- yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) gave 44 mg of enantiomer 2 (chiral HPLC: Rt = 13.6 min) and 42.8 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 11.58 min; 99% ee. Separating method: column: Daicel Chiralpak IB, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 50%/ethanol 50% with 0.2% diethylamine in the ethanol phase; temperature: 40°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: Daicel Chiralpak IB 5 μιη, 250 mm x 4.6 mm; mobile phase: iso-hexane 50%/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.71 min; MS (ESIneg): m/z = 538 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.88), -0.008 (10.34), 0.008 (7.64), 0.146 (0.90), 1.117 (2.12), 1.135 (4.29), 1.153 (2.17), 1.199 (15.72), 1.216 (15.75), 2.328 (0.69), 2.366 (0.81), 2.519 (6.19), 2.524 (5.86), 2.568 (7.57), 2.579 (4.29), 2.597 (1.80), 2.608 (1.06), 2.670 (0.85), 2.710 (0.95), 2.862 (1.43), 2.880 (1.39), 2.899 (0.53), 3.384 (1.41), 3.402 (4.53), 3.420 (4.36), 3.437 (1.22), 3.648 (6.74), 3.659 (11.15), 3.670 (6.26), 7.447 (3.67), 7.454 (3.62), 7.469 (4.16), 7.476 (4.23), 7.559 (2.66), 7.571 (2.82), 7.578 (2.79), 7.590 (2.77), 7.675 (3.30), 7.678 (3.35), 7.697 (2.77), 7.700 (2.59), 7.988 (3.60), 7.992 (3.72), 8.009 (3.97), 8.013 (4.20), 8.119 (7.02), 8.123 (6.53), 8.276 (2.45), 8.280 (3.30), 8.286 (2.91), 8.292 (7.41), 8.300 (3.21), 8.306 (2.52), 8.313 (5.96), 8.427 (6.88), 8.436 (16.00), 8.669 (3.67), 8.673 (3.65), 8.681 (3.62), 8.685 (3.46), 9.078 (5.08), 9.084 (5.01), 10.099 (6.49). Example 7
2-(morpholin-4-yl)-N- {5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (enantiomer 2)
Figure imgf000132_0001
Enantiomer separation of 93.5 mg of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)- yl]-2-(trifluoromethoxy)phenyl}propanamide (Racemate) gave 42.8 mg of enantiomer 1 (chiral HPLC: Rt = 11.58 min) and 44 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 13.6 min; 97% ee. Separating method: column: Daicel Chiralpak IB, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 50%/ethanol 50% with 0.2% diethylamine in the ethanol phase; temperature: 40°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: Daicel Chiralpak IB 5 μιη, 250 mm x 4.6 mm; mobile phase: iso-hexane 50%/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.71 min; MS (ESIneg): m/z = 538 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.149 (0.55), 0.146 (0.63), 1.132 (2.30), 1.150 (4.77), 1.168 (2.45), 1.198 (15.81), 1.216 (16.00), 2.328 (0.62), 2.366 (0.51), 2.578 (5.02), 2.596 (2.00), 2.670 (0.71), 2.709 (0.62), 2.882 (0.64), 2.900 (1.87), 2.918 (1.86), 2.937 (0.66), 3.384 (1.39), 3.401 (4.31), 3.419 (4.21), 3.436 (1.24), 3.658 (14.19), 7.447 (3.25), 7.454 (3.19), 7.469 (3.86), 7.476 (3.80), 7.558 (2.78), 7.569 (3.01), 7.577 (3.02), 7.589 (2.98), 7.676 (4.06), 7.697 (3.30), 7.988 (4.03), 8.009 (4.68), 8.120 (8.36), 8.281 (3.73), 8.292 (6.91), 8.312 (5.05), 8.427 (7.47), 8.435 (15.26), 8.670 (4.23), 8.682 (4.23), 9.079 (6.19), 10.098 (7.82).
Example 8
N-{5-[7-(6-Aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (racemate)
Figure imgf000133_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 70% purity, 119 μηιοΐ), 5-bromopyridin-2-amine (28.6 mg, 97% purity, 161 μιηοΐ), [l,l -bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (4.86 mg, 5.95 μmol) and potassium carbonate (32.9 mg, 238 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (420 μΐ) and 1 ,2-dimethoxyethane (580 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90:10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 38.5 mg (58 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.12 min; MS (ESIneg): m/z = 553 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.49), -0.008 (4.24), 0.008 (4.24), 0.146 (0.51), 1.196 (15.88), 1.213 (16.00), 2.328 (0.82), 2.367 (0.88), 2.564 (7.74), 2.576 (4.36), 2.594 (1.66), 2.605 (0.96), 2.670 (0.80), 2.710 (0.84), 3.380 (1.31), 3.397 (4.47), 3.415 (4.34), 3.432 (1.19), 3.656 (11.76), 3.667
(6.66) , 6.312 (12.70), 6.568 (5.67), 6.590 (5.70), 7.430 (3.61), 7.436 (3.52), 7.452 (4.12), 7.458 (4.22), 7.660 (3.34), 7.664 (3.52), 7.682 (2.87), 7.851 (3.42), 7.855 (3.71), 7.872 (3.65), 7.876 (4.36), 7.901
(3.67) , 7.908 (4.20), 7.914 (8.13), 7.918 (7.31), 7.930 (3.44), 8.177 (7.07), 8.198 (6.02), 8.372 (14.93), 8.401 (6.64), 8.408 (6.54), 8.466 (5.98), 8.472 (5.94), 10.090 (6.94).
Example 9
2-(Morpholin-4-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]propanamide (racemate)
Figure imgf000134_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (200 mg, 70% purity, 238 μηιοΐ), bromobenzene (34 μΐ, 320 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]-dichloropalladium- dichloromethane -complex (9.72 mg, 11.9 μηιοΐ) and potassium carbonate (65.8 mg, 476 μηιοΐ) in N,N- dimethylformamide (210 μΐ), water (840 μΐ) and 1 ,2-dimethoxyethane (1.2 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 97.9 mg (93 %> purity, 71 %> yield) of the desired compound.
LC-MS (Method 6): Rt = 2.12 min; MS (ESIpos): m/z = 539 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.199 (15.65), 1.216 (16.00), 2.327 (0.70), 2.366 (0.55), 2.567 (8.58), 2.578 (4.87), 2.597 (1.88), 2.670 (0.83), 2.710 (0.63), 3.383 (1.45), 3.401 (4.39), 3.418 (4.31), 3.435 (1.30), 3.658 (12.87), 7.368 (0.58), 7.443 (3.64), 7.450 (4.11), 7.465 (5.82), 7.471 (5.29), 7.483 (4.71), 7.501 (3.64), 7.537 (5.84), 7.557 (8.60), 7.574 (3.61), 7.652 (1.15), 7.671 (4.19), 7.693 (2.98), 7.854 (8.55), 7.872 (7.57), 7.929 (3.49), 7.933 (3.76), 7.950 (3.81), 7.954 (4.29), 8.016 (7.45), 8.019 (7.00), 8.203 (0.40), 8.264 (6.67), 8.285 (5.82), 8.415 (14.62), 8.421 (7.77), 8.427 (6.70), 8.461 (0.75), 10.097 (6.92).
Example 10
2-(Morpholin-4-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)
(trifluoromethoxy)phenyl]propanamide (enantiomer 1)
Figure imgf000135_0001
Enantiomer separation of 94 mg of 2-(morpholin-4-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]propanamide (racemate) gave 40 mg of enantiomer 2 (chiral HPLC: Rt = 17.74 min) and 40 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 13.95 min; 99% ee. Separating method: column: YMC Chiralart Cellulose SB, 5 μιη 250 mm x 20 mm; mobile phase: n- heptane 65%/isopropanol 35% with 0.2% diethylamine in the isopropanol phase; temperature: 35°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Cellulose SB 5 μιη, 250 mm x 4.6 mm; mobile phase: n-heptane 65%/isopropanol 35% with 0.2% diethylamine in the isopropanol phase; 45°C; flow rate: 1 ml/min; UV detection: 235 nm.
LC-MS (Method 6): Rt = 2.03 min; MS (ESIpos): m/z = 539 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.94), 1.198 (16.00), 1.216 (15.87), 2.327 (0.55), 2.366 (0.44), 2.519 (4.48), 2.567 (7.93), 2.578 (4.47), 2.597 (1.78), 2.607 (1.05), 2.670 (0.64), 2.709 (0.48), 3.383 (1.44), 3.401 (4.47), 3.418 (4.28), 3.435 (1.23), 3.647 (7.43), 3.658 (12.13), 3.668 (6.77), 7.443 (3.59), 7.450 (3.55), 7.465 (5.33), 7.472 (4.44), 7.482 (4.57), 7.501 (3.48), 7.537 (5.95), 7.556 (8.52), 7.574 (3.56), 7.672 (3.45), 7.693 (2.81), 7.853 (8.58), 7.872 (7.41), 7.929 (3.59), 7.933 (3.69), 7.949 (3.83), 7.954 (4.10), 8.015 (7.36), 8.019 (6.59), 8.264 (6.77), 8.284 (5.84), 8.415 (14.39), 8.421 (7.18), 8.427 (6.28), 10.097 (6.83).
Example 11
2-(Morpholin-4-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]propanamide (enantiomer 2)
Figure imgf000136_0001
Enantiomer separation of 94 mg of 2-(morpholin-4-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]propanamide (racemate) gave 40 mg of enantiomer 1 (chiral HPLC: Rt = 13.95 min) and 40 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 17.74 min; 99% ee. Separating method: column: YMC Chiralart Cellulose SB, 5 μιη 250 mm x 20 mm; mobile phase: n- heptane 65%/isopropanol 35% with 0.2% diethylamine in the isopropanol phase; temperature: 35°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Cellulose SB 5 μιη, 250 mm x 4.6 mm; mobile phase: n-heptane 65%/isopropanol 35% with 0.2% diethylamine in the isopropanol phase; 45°C; flow rate: 1 ml/min; UV detection: 235 nm.
LC-MS (Method 6): Rt = 2.03 min; MS (ESIpos): m/z = 539 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.199 (15.73), 1.216 (16.00), 2.328 (0.54), 2.366 (0.46), 2.567 (8.19), 2.578 (4.57), 2.597 (1.80), 2.608 (1.08), 2.669 (0.66), 2.710 (0.52), 3.383 (1.36), 3.401 (4.38), 3.418 (4.25), 3.436 (1.26), 3.658 (12.54), 7.444 (3.40), 7.450 (3.35), 7.465 (5.25), 7.472 (4.35), 7.483 (4.52), 7.501 (3.54), 7.537 (5.94), 7.557 (8.74), 7.575 (3.70), 7.675 (3.56), 7.694 (2.96), 7.854 (8.74), 7.873 (7.67), 7.929 (3.53), 7.933 (3.75), 7.950 (3.87), 7.954 (4.30), 8.016 (7.51), 8.020 (6.99), 8.264 (6.70), 8.285 (5.90), 8.416 (14.62), 8.421 (7.37), 8.427 (6.48), 10.097 (7.11).
Example 12
2-(Morpholin-4-yl)-N-{5-[4-oxo-7-(pyrimidin-5-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000137_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (Racemate) (100 mg, 70% purity, 119 μηιοΐ), 5-bromopyrimidine (25.5 mg, 161 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.86 mg, 5.95 μηιοΐ) and potassium carbonate (32.9 mg, 238 μηιοΐ) in N,N-dimethylformamide (100 μΐ), water (420 μΐ) and 1 ,2-dimethoxyethane (580 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for 1 h. The reaction mixture was partitioned between 4 ml dichloromethane and 1 ml of water. After phase separation the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were evaporated and the residue was chromatographed over a silica column eluting with a gradient of dichloromethane/methanol from 100: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to provide 54.7 mg (85 % yield) of the desired compound.
LC-MS (Method 6): Rt = 1.37 min; MS (ESIpos): m/z = 541 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.198 (8.97), 1.216 (9.04), 2.328 (0.50), 2.567 (4.70), 2.579 (2.62), 2.598 (1.02), 2.670 (0.55), 3.385 (0.76), 3.402 (2.49), 3.420 (2.45), 3.437 (0.67), 3.658 (7.11), 7.451 (1.91), 7.458 (1.88), 7.473 (2.26), 7.480 (2.26), 7.677 (2.01), 7.699 (1.72), 8.056 (2.07), 8.060 (2.02), 8.077 (2.36), 8.081 (2.39), 8.243 (4.30), 8.246 (4.00), 8.314 (3.99), 8.335 (3.33), 8.432 (3.72), 8.438 (3.63), 8.453 (7.85), 9.286 (6.09), 9.342 (16.00), 10.099 (4.02).
Example 13
N-{5-[7-(l -Methyl-lH-pyrazol-4-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2- (morpholin-4-yl)propanamide (racemate)
Figure imgf000138_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (400 mg, 60% purity, 408 μηιοΐ), 4-bromo-l -methyl- lH-pyrazole (57 μΐ, 550 μmol), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (16.7 mg, 20.4 μηιοΐ) and potassium carbonate (113 mg, 816 μηιοΐ) in N,N-dimethylformamide (360 μΐ), water (1.4 ml) and 1,2-dimethoxyethane (2.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100: 1 to 87: 13. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 105 mg (47 % yield) of the desired compound.
LC-MS (Method 6): Rt = 1.44 min; MS (ESIpos): m/z = 543 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.90), 0.008 (2.10), 1.194 (7.78), 1.212 (7.73), 2.073 (1.59), 2.563 (3.79), 2.575 (2.13), 2.593 (0.83), 2.603 (0.48), 3.377 (0.69), 3.395 (2.21), 3.412 (2.13), 3.430 (0.57), 3.645 (3.59), 3.655 (5.80), 3.906 (16.00), 7.424 (1.85), 7.431 (1.81), 7.446 (2.05), 7.453 (2.09), 7.655 (1.68), 7.658 (1.71), 7.676 (1.40), 7.680 (1.30), 7.813 (1.84), 7.818 (1.90), 7.834 (1.95), 7.838 (2.11), 7.929 (3.60), 7.933 (3.40), 8.116 (5.29), 8.140 (3.40), 8.161 (2.90), 8.353 (7.28), 8.391 (3.23), 8.398 (3.17), 8.431 (4.91), 10.086 (3.25).
Example 14
N-{5-[7-(l -Methyl-lH-pyrazol-4-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2- (morpholin-4-yl)propanamide (enantiomer 1)
Figure imgf000139_0001
Enantiomer separation of 100 mg of N-{5-[7-(l -methyl-lH-pyrazol-4-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(morpholin-4-yl)propanamide (racemate) gave 40 mg of enantiomer 2 (chiral HPLC: Rt = 12.38 min) and 33 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 11.64 min; 99% ee.
Separating method: column: YMC Chiralart Cellulose SB, 5 μιη 250 mm x 20 mm; mobile phase: n- heptane 50%/ethanol 50% with 0.2%> diethylamine in the ethanol phase; temperature: 55°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Cellulose SB 5 μιη, 250 mm x 4.6 mm; mobile phase: n-heptane 50%>/ethanol 50% with 0.2%) diethylamine in the ethanol phase; 50°C; flow rate: 1 ml/min; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 543 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.126 (0.51), 1.144 (1.06), 1.162 (0.53), 1.194 (7.44), 1.212 (7.58), 2.073 (2.36), 2.328 (0.45), 2.592 (0.81), 2.603 (0.48), 2.670 (0.51), 3.378 (0.65), 3.395 (2.14), 3.412 (2.10), 3.430 (0.61), 3.645 (3.04), 3.655 (5.37), 3.906 (16.00), 7.424 (1.72), 7.431 (1.72), 7.446 (1.94), 7.453 (2.08), 7.655 (1.54), 7.658 (1.65), 7.677 (1.34), 7.680 (1.29), 7.814 (1.63), 7.818 (1.82), 7.835 (1.85), 7.838 (2.05), 7.929 (3.46), 7.933 (3.42), 8.116 (5.34), 8.140 (3.36), 8.161 (2.94), 8.353 (7.27), 8.391 (3.12), 8.397 (3.20), 8.431 (4.97), 10.086 (3.18).
Example 15
N-{5-[7-(3-Fluoropyridin-2-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (racemate)
Figure imgf000140_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 102 μηιοΐ), 2-bromo-3-fluoropyridine (24.2 mg, 138 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.33 mg, 10.2 μηιοΐ) and potassium carbonate (28.2 mg, 204 μηιοΐ) in N,N-dimethylformamide (90 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 89: 11. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 27.0 mg (97 % purity, 46 % yield) of the desired compound.
LC-MS (Method 6): Rt = 1.71 min; MS (ESIpos): m/z = 558 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.149 (0.79), 0.146 (0.86), 1.199 (14.13), 1.217 (14.30), 2.327 (1.18), 2.568 (8.21), 2.580 (4.60), 2.597 (1.97), 2.670 (1.28), 3.384 (1.52), 3.401 (4.01), 3.419 (3.86), 3.436 (1.18), 3.659 (12.31), 7.455 (3.07), 7.461 (3.15), 7.477 (3.59), 7.483 (3.71), 7.591 (1.50), 7.601 (2.61), 7.612 (3.24), 7.622 (3.07), 7.632 (1.79), 7.680 (3.47), 7.699 (2.83), 7.923 (2.19), 7.952 (2.36), 7.975 (1.94), 8.151 (3.22), 8.172 (4.01), 8.254 (6.37), 8.329 (6.24), 8.350 (4.96), 8.434 (16.00), 8.649 (3.49), 8.660 (3.42), 10.099 (6.41).
Example 16
N-{5-[7-(5-Chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (Racemate)
Figure imgf000141_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 102 μηιοΐ), 3-bromo-5-chloropyridine (26.5 mg, 138 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.33 mg, 10.2 μηιοΐ) and potassium carbonate (28.2 mg, 204 μηιοΐ) in N,N-dimethylformamide (90 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0,2% ammonia) to deliver 24.0 mg (41 % yield) of the desired compound.
LC-MS (Method 6): Rt = 1.81 min; MS (ESIpos): m/z = 574 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.23), -0.008 (11.56), 0.008 (11.52), 0.069 (0.75), 0.146 (1.23), 1.198 (15.70), 1.216 (16.00), 2.328 (1.57), 2.567 (8.17), 2.579 (4.62), 2.598 (1.83), 2.670 (1.57), 3.385 (1.49), 3.402 (4.40), 3.419 (4.33), 3.437 (1.19), 3.659 (12.42), 7.448 (3.43), 7.455 (3.51), 7.470 (4.03), 7.477 (4.14), 7.679 (3.51), 7.698 (2.98), 8.032 (3.47), 8.036 (3.66), 8.052 (3.88), 8.057 (4.25), 8.198 (7.16), 8.202 (7.09), 8.288 (6.90), 8.309 (5.78), 8.428 (6.56), 8.434 (6.60), 8.445 (14.40), 8.478 (4.18), 8.483 (7.57), 8.488 (4.48), 8.729 (6.19), 8.735 (5.86), 9.055 (7.27), 9.059 (7.24), 10.099 (6.94).
Example 17
N-{5-[7-(4-Methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (enantiomer 1)
Figure imgf000142_0001
Enantiomer separation of 93 mg of N-{5-[7-(4-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(morpholin-4-yl)propanamide (racemate) gave 42.2 mg of enantiomer 2 (chiral HPLC: Rt = 14.4 min) and 38.9 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 10.0 min; 100% ee.
Separating method: column: Kromasil 5-CelluCoat, 5 μιη 250 mm x 21.1 mm; mobile phase: n-heptane 50%/ethanol 50% with 0.2% diethylamine in the ethanol phase; temperature: rt; flow rate: 25 ml/min; UV detection: 230 nm.
Analysis: column: Phenomenex Cellulose-1 3 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%o/ethanol 50%> with 0.2%> diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 220 nm.
LC-MS (Method 6): Rt = 1.32 min; MS (ESIneg): m/z = 552 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.140 (0.66), 1.158 (1.33), 1.176 (0.95), 1.202 (6.64), 1.220 (6.73), 2.322 (16.00), 2.569 (3.59), 2.600 (0.88), 3.388 (0.60), 3.405 (1.41), 3.423 (1.35), 3.440 (0.48), 3.661 (6.11), 7.411 (1.94), 7.423 (1.94), 7.447 (1.68), 7.453 (1.65), 7.468 (1.91), 7.475 (1.87), 7.641 (2.01), 7.645 (2.03), 7.661 (2.12), 7.665 (2.26), 7.678 (1.81), 7.682 (1.79), 7.700 (1.47), 7.773 (3.60), 7.776 (3.35), 8.275 (3.33), 8.295 (3.07), 8.429 (9.08), 8.491 (1.39), 8.512 (1.18), 10.104 (2.47).
Example 18
N-{5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin-4- yl)propanamide (racemate)
Figure imgf000143_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 102 μηιοΐ), 1 -bromo-2-fluorobenzene (24.1 mg, 138 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.33 mg, 10.2 μηιοΐ) and potassium carbonate (28.2 mg, 204 μηιοΐ) in N,N-dimethylformamide (90 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 33.0 mg (95 % purity, 55 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.02 min; MS (ESIpos): m/z = 557 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.36), -0.008 (11.89), 0.008 (13.38), 0.146 (1.45), 1.199 (14.60), 1.217 (14.87), 2.327 (1.45), 2.366 (0.41), 2.567 (7.32), 2.579 (4.16), 2.598 (1.58), 2.608 (1.04), 2.669 (1.58), 2.709 (0.50), 3.384 (1.36), 3.401 (4.11), 3.419 (4.11), 3.437 (1.18), 3.659 (10.98), 7.373 (2.08), 7.382 (1.94), 7.391 (4.34), 7.403 (2.89), 7.408 (4.47), 7.429 (2.35), 7.442 (3.30), 7.449 (3.30), 7.464 (3.89), 7.470 (4.07), 7.512 (1.18), 7.525 (1.99), 7.546 (1.67), 7.559 (0.72), 7.675 (2.98), 7.678 (3.21), 7.684 (2.76), 7.697 (2.94), 7.704 (4.29), 7.708 (3.48), 7.724 (1.58), 7.728 (1.54), 7.788 (3.25), 7.809 (3.57), 7.907 (5.88), 8.208 (0.45), 8.279 (5.92), 8.300 (5.51), 8.423 (16.00), 8.431 (6.10), 8.461 (0.86), 10.099 (6.06).
Example 19
N-{5-[7-(3-Fluoropyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (racemate)
Figure imgf000144_0001
A mixture of 2-(Morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 102 μηιοΐ), 4-bromo-3-fluoropyridine (24.2 mg, 138 μmol), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.33 mg, 10.2 μηιοΐ) and potassium carbonate (28.2 mg, 204 μηιοΐ) in N,N-dimethylformamide (90 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 38.0 mg (96 % purity, 64 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.62 min; MS (ESIpos): m/z = 558 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.85), -0.008 (7.08), 0.008 (7.20), 0.146 (0.77), 1.199 (15.60), 1.216 (16.00), 2.327 (1.00), 2.567 (7.73), 2.578 (4.29), 2.597 (1.72), 2.670 (1.07), 3.384 (1.50), 3.402 (4.44), 3.419 (4.24), 3.437 (1.25), 3.658 (11.86), 7.447 (3.49), 7.453 (3.49), 7.469 (4.14), 7.475 (4.24), 7.678 (3.34), 7.682 (3.49), 7.700 (2.79), 7.704 (2.72), 7.791 (3.09), 7.804 (3.56), 7.808 (3.49), 7.821 (3.17), 7.875 (3.66), 7.895 (3.99), 8.040 (6.85), 8.328 (6.78), 8.349 (6.08), 8.432 (6.48), 8.439 (6.63), 8.453 (14.60), 8.593 (5.13), 8.605 (4.93), 8.718 (0.45), 8.757 (6.55), 8.763 (6.55), 10.100 (6.63).
Example 20
2-(6-Oxa-3-azabicyclo[3.1.1]hept-3-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000145_0001
A mixture of 2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (110 mg, 60% purity, 110 μηιοΐ), 3-bromopyridine (23.4 mg, 148 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.98 mg, 11.0 μηιοΐ) and potassium carbonate (30.4 mg, 220 μηιοΐ) in N,N-dimethylformamide (97 μΐ), water (390 μΐ) and 1,2-dimethoxyethane (530 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2%> ammonia) and the resulting product was further purified as follows. Instrument: Waters Prep LC/MS System; column: XBridge C18 5μηι 100x30 mm; mobile phase: water/acetonitrile plus 5 ml of 2%> ammonia in water (eluent B); flow: 65 ml/min, room temperature, detection wavelength 200-400 nm. Gradient profile: 0 to 2 min 10%> eluent B, 2 to 2,2 min to 30%> eluent B, 2,2 to 7 min to 70%> eluent B, 7 to 7,5 min to 92%> eluent B, 7,5 to 9 min at 92%o eluent B. This purification provided 11.6 mg (95 %> purity, 18 %> yield) of the title compound.
LC-MS (Method 6): Rt = 1.37 min; MS (ESIneg): m/z = 550 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.150 (1.74), -0.008 (14.40), 0.146 (1.60), 1.301 (15.82), 1.318 (16.00), 2.073 (1.46), 2.337 (4.48), 2.358 (4.25), 2.669 (1.60), 2.710 (0.82), 2.926 (13.39), 2.956
(3.06) , 2.972 (1.51), 2.986 (3.20), 3.013 (5.17), 3.082 (4.11), 3.110 (2.29), 3.551 (1.33), 3.568 (4.39), 3.585 (4.34), 3.603 (1.23), 4.476 (5.76), 4.489 (5.67), 7.454 (3.57), 7.460 (3.66), 7.476 (3.98), 7.482
(4.07) , 7.559 (2.79), 7.571 (2.93), 7.578 (2.97), 7.591 (3.06), 7.657 (3.61), 7.676 (2.74), 7.988 (3.57), 7.993 (3.89), 8.009 (3.98), 8.014 (4.48), 8.120 (7.36), 8.124 (7.22), 8.282 (3.38), 8.287 (2.79), 8.293 (7.73), 8.302 (3.43), 8.314 (6.35), 8.372 (6.58), 8.378 (6.40), 8.440 (14.35), 8.669 (3.93), 8.673 (4.02), 8.681 (3.89), 8.685 (3.89), 9.079 (5.71), 9.084 (5.85), 9.864 (7.13).
Example 21
2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin
(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000146_0001
A mixture of 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (164 mg, 60% purity, 160 μηιοΐ), 3-bromopyridine (34.1 mg, 216 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (13.1 mg, 16.0 μηιοΐ) and potassium carbonate (44.2 mg, 320 μηιοΐ) in N,N-dimethylformamide (140 μΐ), water (560 μΐ) and 1,2-dimethoxyethane (770 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was then filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 45.0 mg (98 % purity, 49 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.74 min; MS (ESIneg): m/z = 564 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.91), -0.008 (7.41), 0.008 (7.79), 0.069 (0.40), 0.146 (0.96), 1.158 (15.77), 1.175 (16.00), 1.804 (4.56), 1.816 (3.15), 1.920 (1.01), 1.944 (3.15), 1.962 (1.86), 1.989 (2.54), 2.014 (0.78), 2.328 (0.83), 2.366 (0.53), 2.590 (10.94), 2.670 (0.96), 2.710 (0.58), 3.293 (2.12), 3.328 (5.74), 3.345 (1.46), 4.267 (5.34), 7.450 (3.75), 7.456 (3.78), 7.472 (4.33), 7.478 (4.46), 7.559 (2.97), 7.571 (3.07), 7.579 (3.07), 7.591 (3.17), 7.671 (3.28), 7.675 (3.45), 7.693 (2.80), 7.697 (2.62), 7.988 (3.73), 7.992 (3.96), 8.009 (4.16), 8.013 (4.59), 8.119 (7.28), 8.124 (7.08), 8.276 (2.32), 8.281 (3.35), 8.286 (2.87), 8.292 (7.71), 8.302 (3.45), 8.306 (2.67), 8.313 (6.40), 8.436 (15.12), 8.455 (6.58), 8.462 (6.55), 8.669 (3.91), 8.673 (4.01), 8.681 (3.93), 8.685 (3.88), 9.079 (5.69), 9.084 (5.62), 9.725 (7.36).
Example 22
N-{5-[7-(5-Methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(morpholin- 4-yl)cyclopropanecarboxamide
Figure imgf000147_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (295 mg, 72% purity, 354 μηιοΐ), 3-bromo-5-methylpyridine (55 μΐ, 480 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (14.4 mg, 17.7 μηιοΐ) and potassium carbonate (97.8 mg, 708 μηιοΐ) in N,N-dimethylformamide (310 μΐ), water (1.2 ml) and 1,2-dimethoxyethane (1.7 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 119 mg (60 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.90 min; MS (ESIpos): m/z = 566 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.00), 0.008 (1.04), 0.067 (0.76), 1.117 (1.32), 1.130 (3.69), 1.137 (4.17), 1.147 (1.95), 1.234 (0.55), 1.273 (1.83), 1.283 (4.08), 1.291 (3.43), 1.303 (1.37), 2.328 (0.53), 2.419 (16.00), 2.472 (5.64), 2.483 (4.87), 2.670 (0.53), 3.708 (5.47), 7.427 (2.13), 7.434 (2.11), 7.449 (2.37), 7.456 (2.43), 7.702 (1.79), 7.706 (1.85), 7.724 (1.60), 7.728 (1.48), 7.971 (1.97), 7.975 (2.04), 7.992 (2.20), 7.996 (2.34), 8.097 (4.10), 8.101 (3.92), 8.120 (3.04), 8.275 (3.87), 8.296 (3.32), 8.424 (8.63), 8.513 (3.09), 8.516 (3.08), 8.575 (4.22), 8.581 (4.17), 8.868 (3.29), 8.873 (3.18), 10.628 (3.78).
Example 23
l-(Morpholin-4-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]cyclopropanecarboxamide
Figure imgf000148_0001
l-(Morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (CAS 1257236-65-9) (32.3 mg, 155 μηιοΐ) was suspended in dichloromethane (5.0 ml) and l -chloro-N,N,2-trimethylprop-l -en-l-amine (86 μΐ, 96 % purity, 620 μιηοΐ) was added. This mixture was stirred at rt for 2 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (46 ml) and the mixture was once more evaporated. The residue was then suspended in dichloromethane (46 ml) and pyridine (38 μΐ, 470 μιηοΐ) and 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-phenylquinazolin-4(3H)-one (65.0 mg, 95% purity, 155 μιηοΐ) were added. This reaction mixture was stirred for 18 h at rt. The mixture was evaporated and the crude material was purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to provide 31.1 mg (97 % purity, 35 % yield) of the title product.
LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 551 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), -0.008 (6.40), 0.008 (4.72), 0.146 (0.66), 1.118 (3.33), 1.130 (7.91), 1.138 (8.77), 1.148 (3.97), 1.189 (0.70), 1.205 (0.43), 1.232 (0.62), 1.272 (3.63), 1.282 (8.23), 1.290 (6.80), 1.302 (2.73), 2.185 (0.79), 2.328 (0.83), 2.366 (0.77), 2.471 (11.39), 2.482 (9.98), 2.523 (2.56), 2.670 (0.87), 2.710 (0.75), 2.960 (1.64), 3.707 (11.11), 7.424 (4.10), 7.431 (3.99), 7.446 (4.63), 7.453 (4.76), 7.462 (1.66), 7.481 (5.03), 7.499 (3.99), 7.535 (6.38), 7.555 (9.36), 7.572 (3.95), 7.700 (3.63), 7.703 (3.63), 7.722 (3.14), 7.725 (2.88), 7.851 (9.04), 7.869 (8.28), 7.925 (3.95), 7.929 (4.14), 7.946 (4.27), 7.950 (4.69), 8.011 (8.17), 8.016 (7.34), 8.258 (7.55), 8.278 (6.63), 8.409 (16.00), 8.461 (0.47), 8.571 (7.81), 8.577 (7.62), 10.627 (7.47).
Example 24
N-{5-[7-(2-Methylphenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(morpholin-4- yl)cyclopropanecarboxamide
Figure imgf000149_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (70.0 mg, 64% purity, 74.6 μηιοΐ), l-bromo-2-methylbenzene (12 μΐ, 100 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (3.05 mg, 3.73 μηιοΐ) and potassium carbonate (20.6 mg, 149 μηιοΐ) in N,N-dimethylformamide (66 μΐ), water (260 μΐ) and 1,2-dimethoxyethane (360 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0,2% ammonia) to deliver 28.2 mg (67 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.27 min; MS (ESIpos): m/z = 565 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.121 (1.11), 1.133 (3.19), 1.141 (3.52), 1.151 (1.59), 1.233 (0.47), 1.274 (1.54), 1.284 (3.49), 1.291 (2.94), 1.304 (1.14), 2.283 (16.00), 2.473 (4.93), 3.709 (4.86), 7.303 (0.65), 7.313 (2.07), 7.318 (3.24), 7.333 (1.97), 7.356 (2.79), 7.363 (3.76), 7.369 (2.83), 7.374 (1.95), 7.423 (1.61), 7.430 (1.59), 7.445 (1.86), 7.452 (1.85), 7.578 (1.71), 7.582 (1.78), 7.599 (1.76), 7.603 (1.92), 7.671 (3.32), 7.675 (3.10), 7.703 (1.49), 7.707 (1.50), 7.725 (1.30), 7.729 (1.23), 8.236 (2.97), 8.257 (2.80), 8.401 (6.18), 8.574 (3.23), 8.581 (3.13), 10.630 (3.26).
Example 25
N-{5-[7-(6-Aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(morpholin- 4-yl)cyclopropanecarboxamide
Figure imgf000150_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (95.0 mg, 64% purity, 101 μηιοΐ), 5-bromopyridin-2-amine (24.4 mg, 97 % purity, 137 μιηοΐ), [l,l-bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (4.13 mg, 5.06 μmol) and potassium carbonate (28.0 mg, 203 μιηοΐ) in N,N-dimethylformamide (89 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 20.8 mg (94 % purity, 34 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 567 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.55), 0.146 (0.55), 1.116 (2.66), 1.128 (7.44), 1.135 (8.13), 1.146 (3.73), 1.270 (3.49), 1.279 (8.09), 1.287 (6.92), 1.299 (2.72), 2.157 (1.34), 2.328 (0.99), 2.366 (0.85), 2.469 (11.88), 2.480 (9.79), 2.670 (0.95), 2.710 (0.79), 3.706 (11.54), 6.311 (14.42), 6.566 (6.39), 6.588 (6.33), 7.411 (3.87), 7.418 (3.87), 7.433 (4.36), 7.439 (4.44), 7.692 (3.69), 7.711 (3.22), 7.848 (3.67), 7.852 (4.08), 7.869 (3.93), 7.873 (4.77), 7.899 (4.04), 7.910 (9.15), 7.914 (8.07), 7.920 (4.16), 7.927 (3.81), 8.171 (7.60), 8.192 (6.51), 8.365 (16.00), 8.463 (6.73), 8.469 (6.71), 8.552 (7.95), 8.558 (7.91), 10.620 (7.83).
Example 26
l-(Morpholin-4-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin- (trifluoromethoxy)phenyl}cyclopropanecarboxamide
Figure imgf000151_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (95.0 mg, 64% purity, 101 μιηοΐ), 3-bromopyridine (13 μΐ, 98% purity, 140 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.13 mg, 5.06 μιηοΐ) and potassium carbonate (28.0 mg, 203 μιηοΐ) in N,N-dimethylformamide (89 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 29.0 mg (98 % purity, 51 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.86 min; MS (ESIpos): m/z = 552 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.30), 0.008 (3.34), 1.118 (2.81), 1.130 (8.07), 1.138 (9.10), 1.148 (4.40), 1.190 (0.41), 1.231 (0.55), 1.273 (3.91), 1.283 (8.75), 1.291 (7.40), 1.303 (2.93), 2.328 (0.59), 2.367 (0.72), 2.472 (12.48), 2.482 (9.90), 2.671 (0.61), 2.711 (0.68), 3.708 (12.37), 7.429 (4.10), 7.435 (4.08), 7.451 (4.65), 7.457 (4.79), 7.556 (3.38), 7.568 (3.48), 7.576 (3.50), 7.588 (3.54), 7.703 (3.69), 7.706 (3.79), 7.725 (3.26), 7.728 (3.09), 7.984 (4.08), 7.988 (4.32), 8.004 (4.57), 8.009 (4.96), 8.114 (8.32), 8.118 (7.91), 8.272 (2.68), 8.277 (4.02), 8.285 (8.67), 8.292 (3.03), 8.298 (3.91), 8.306 (7.21), 8.429 (16.00), 8.578 (7.89), 8.584 (7.85), 8.667 (4.43), 8.671 (4.49), 8.679 (4.43), 8.683 (4.34), 9.075 (6.62), 9.080 (6.49), 10.628 (8.01).
Example 27
N-{5-[7-(4-Methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(morpholin- 4-yl)cyclopropanecarboxamide
Figure imgf000152_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (95.0 mg, 64% purity, 101 μηιοΐ), 3-bromo-4-methylpyridine (15 μΐ, 98% purity, 140 μηιοΐ), [l,l -bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (4.13 mg, 5.06 μmol) and potassium carbonate (28.0 mg, 203 μιηοΐ) in N,N-dimethylformamide (89 μΐ), water (360 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2%> ammonia) to deliver 41.0 mg (98 % purity, 70 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.76 min; MS (ESIpos): m/z = 566 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.121 (1.18), 1.134 (3.40), 1.141 (3.80), 1.151 (1.72), 1.275 (1.65), 1.285 (3.71), 1.292 (3.17), 1.305 (1.25), 2.321 (16.00), 2.366 (0.43), 2.474 (5.50), 2.670 (0.60), 2.710 (0.47), 3.710 (5.29), 7.406 (2.41), 7.419 (2.57), 7.426 (1.90), 7.433 (1.76), 7.448 (1.92), 7.455 (2.05), 7.638 (1.85), 7.642 (1.99), 7.659 (1.88), 7.662 (2.14), 7.710 (1.72), 7.728 (1.43), 7.770 (3.66), 7.773 (3.62), 8.269 (3.28), 8.289 (3.04), 8.423 (6.99), 8.483 (5.65), 8.506 (3.31), 8.519 (3.19), 8.579 (3.38), 8.586 (3.42), 10.632 (3.51).
Example 28
N-{5-[7-(2-Fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(morpholin-4- yl)cyclopropanecarboxamide
Figure imgf000153_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (70.0 mg, 127 μmol), (2-fluorophenyl)boronic acid (23.9 mg, 171 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (10.3 mg, 12.7 μιηοΐ) and potassium carbonate (35.0 mg, 253 μιηοΐ) in N,N-dimethylformamide (110 μΐ), water (440 μΐ) and 1, 2 -dimethoxy ethane (610 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 38.0 mg (95 % purity, 50 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.22 min; MS (ESIpos): m/z = 569 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.149 (0.42), -0.022 (0.42), -0.008 (3.24), 0.008 (3.26), 1.120 (2.48), 1.132 (7.04), 1.139 (7.86), 1.150 (3.68), 1.234 (0.97), 1.273 (3.39), 1.283 (7.72), 1.290 (6.43), 1.303 (2.63), 2.367 (0.71), 2.472 (10.55), 2.483 (9.04), 2.710 (0.69), 3.708 (10.37), 7.370 (2.46), 7.381 (2.29), 7.389 (5.1 1), 7.401 (3.53), 7.406 (5.42), 7.423 (4.88), 7.430 (6.14), 7.445 (4.48), 7.452 (4.67), 7.506 (1.30), 7.510 (1.41), 7.519 (1.51), 7.524 (2.33), 7.530 (2.02), 7.544 (2.02), 7.549 (1.03), 7.558 (0.86), 7.562 (0.86), 7.681 (2.10), 7.685 (2.08), 7.702 (6.27), 7.706 (6.60), 7.721 (3.28), 7.725 (4.69), 7.784 (3.89), 7.805 (4.16), 7.904 (7.15), 8.273 (7.23), 8.293 (6.64), 8.416 (16.00), 8.576 (7.67), 8.583 (7.57), 10.628 (7.04).
Example 29
N-{5-[7-(5-Chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l -(morpholin- 4-yl)cyclopropanecarboxamide
Figure imgf000154_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (185 mg, 70% purity, 216 μηιοΐ), 3-bromo-5-chloropyridine (56.0 mg, 291 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.81 mg, 10.8 μηιοΐ) and potassium carbonate (59.6 mg, 431 μηιοΐ) in N,N-dimethylformamide (190 μΐ), water (760 μΐ) and 1,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was triturated in diethylether, filetered, rinsed with more diethylether and dried under high vacuum. This provided 90.0 mg (71 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.17 min; MS (ESIpos): m/z = 586 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.137 (9.11), 1.285 (8.96), 2.327 (3.18), 2.672 (2.99), 3.710 (16.00), 7.455 (5.44), 7.708 (4.13), 8.050 (4.40), 8.198 (6.78), 8.283 (4.25), 8.303 (3.83), 8.439 (7.31), 8.480 (6.16), 8.583 (5.78), 8.730 (5.01), 9.056 (6.20), 10.631 (6.24).
Example 30
N-{5-[7-(3-Methyl-l-oxidopyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(4- methylpiperazin- 1 -yl)cyclopropanecarboxamide
Figure imgf000154_0002
A mixture of l-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (100 mg, 53% purity, 86.4 μηιοΐ), 4-bromo-3-methylpyridine 1-oxide (21.9 mg, 117 μηιοΐ), [l,l -bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (3.53 mg, 4.32 μηιοΐ) and potassium carbonate (23.9 mg, 173 μιηοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1, 2 -dimethoxy ethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 12.0 mg (96 % purity, 22 % yield) of the title compound.
LC-MS (Method 6): Rt = 0.90 min; MS (ESIneg): m/z = 593 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.42), 0.008 (2.52), 1.110 (1.19), 1.123 (3.39), 1.130 (3.88), 1.140 (1.89), 1.242 (1.78), 1.252 (3.86), 1.259 (3.22), 1.272 (1.31), 2.205 (6.55), 2.251 (16.00), 2.328 (0.78), 2.367 (0.89), 2.670 (0.76), 2.710 (0.68), 7.409 (4.81), 7.414 (2.23), 7.426 (3.71), 7.430 (2.71), 7.436 (2.23), 7.639 (2.04), 7.643 (2.18), 7.659 (2.14), 7.663 (2.35), 7.697 (1.69), 7.701 (1.78), 7.719 (1.50), 7.723 (1.44), 7.785 (3.81), 7.788 (3.86), 8.170 (1.67), 8.173 (1.76), 8.190 (1.72), 8.259 (3.64), 8.279 (3.43), 8.322 (3.09), 8.424 (8.07), 8.618 (1.91), 8.624 (1.95), 10.658 (1.78).
Example 31
1 -(4-Methylpiperazin- 1 -yl)-N-[5-(4-oxo-7-phenylquinazolin
(trifluoromethoxy)phenyl]cyclopropanecarboxamide
Figure imgf000155_0001
1 -(4-Methylpiperazin- 1 -yl)cyclopropanecarboxylic acid hydrochloride (WO2014147021A2, Intermediate 42) (111 mg, 503 μιηοΐ) was suspended in dichloromethane (16 ml) and 1 -chloro-N,N,2- trimethylprop-l -en-l-amine (280 μΐ, 96%> purity, 2.0 mmol) was added. This mixture was stirred at rt for
2 h and then evaporated under reduced pressure. The residue was again suspended in dichloromethane (16 ml) and the mixture was once more evaporated. The residue was then suspended in dichloromethane (16 ml) and pyridine (120 μΐ, 1.5 mmol) and 3-[3-amino-4-(trifluoromethoxy)phenyl]-7- phenylquinazolin-4(3H)-one (200 mg, 503 μιηοΐ) were added. This reaction mixture was stirred for 18 h at rt. The mixture was evaporated and the crude material was purified twice by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2%> ammonia) to provide 60.0 mg (21 % yield) of the title product. LC-MS (Method 6): Rt = 1.42 min; MS (ESIneg): m/z = 562 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.73), -0.008 (6.31), 0.008 (7.24), 0.146 (0.73), 1.116 (2.12), 1.128 (5.78), 1.135 (6.90), 1.145 (3.32), 1.239 (3.45), 1.249 (7.17), 1.256 (5.84), 1.269 (2.39), 2.229 (3.19), 2.328 (2.12), 2.366 (1.59), 2.670 (2.06), 2.711 (1.33), 7.418 (2.59), 7.424 (2.66), 7.440 (2.99), 7.446 (3.05), 7.462 (1.46), 7.481 (4.71), 7.499 (3.85), 7.536 (6.04), 7.555 (9.03), 7.573 (3.78), 7.693 (3.32), 7.697 (3.45), 7.715 (2.92), 7.852 (8.50), 7.869 (7.83), 7.926 (3.72), 7.930 (4.18), 7.946 (4.05), 7.951 (4.78), 8.011 (7.83), 8.016 (7.37), 8.258 (7.37), 8.278 (6.44), 8.409 (16.00), 8.599 (1.46), 10.629 (0.93).
Example 32
1 -(4-Methylpiperazin-l -yl)-N- {5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}cyclopropanecarboxamide
Figure imgf000156_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (100 mg, 53% purity, 86.4 μηιοΐ), 3-bromopyridine (18.4 mg, 117 μπιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (3.53 mg, 4.32 μπιοΐ) and potassium carbonate (23.9 mg, 173 μιηοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2-dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 30.0 mg (97 % purity, 60 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.59 min; MS (ESIneg): m/z = 563 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (3.02), 0.008 (3.06), 1.110 (1.35), 1.123 (3.77), 1.131 (4.36), 1.140 (2.18), 1.242 (2.05), 1.252 (4.24), 1.260 (3.45), 1.272 (1.41), 2.198 (16.00), 2.328 (0.70), 2.367 (0.85), 2.670 (0.68), 2.710 (0.59), 7.414 (2.15), 7.421 (2.17), 7.436 (2.36), 7.443 (2.44), 7.556 (1.67), 7.568 (1.71), 7.576 (1.73), 7.588 (1.79), 7.697 (1.80), 7.701 (1.88), 7.719 (1.67), 7.723 (1.71), 7.983 (2.06), 7.988 (2.20), 8.004 (2.30), 8.009 (2.56), 8.114 (4.14), 8.118 (4.08), 8.272 (1.30), 8.277 (1.97), 8.285 (4.47), 8.292 (1.48), 8.298 (1.95), 8.306 (3.74), 8.430 (8.73), 8.629 (4.11), 8.635 (4.12), 8.667 (2.32), 8.671 (2.36), 8.679 (2.30), 8.682 (2.30), 9.075 (3.26), 9.080 (3.21), 10.665 (3.85).
Example 33
l-(4-Methylpiperazin-l-yl)-N-{5-[7-(5-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropanecarboxamide
Figure imgf000157_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (80.0 mg, 57% purity, 74.3 μηιοΐ), 3-bromo-5-methylpyridine (17.3 mg, 100 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (6.07 mg, 7.43 μηιοΐ) and potassium carbonate (20.5 mg, 149 μηιοΐ) in N,N-dimethylformamide (66 μΐ), water (260 μΐ) and 1,2-dimethoxyethane (360 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 97: 13. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 17.0 mg (40 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.10 min; MS (ESIneg): m/z = 577 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.124 (4.59), 1.251 (4.84), 2.212 (8.26), 2.418 (16.00), 2.467 (7.42), 7.416 (2.14), 7.422 (1.73), 7.438 (2.48), 7.444 (1.97), 7.695 (2.27), 7.717 (2.01), 7.971 (2.46), 7.975 (1.95), 7.991 (2.73), 7.996 (2.24), 8.096 (5.07), 8.120 (3.71), 8.275 (3.29), 8.295 (2.86), 8.421 (4.20), 8.424 (7.03), 8.512 (3.92), 8.615 (3.05), 8.868 (4.20), 10.647 (2.53).
Example 34
l-(4-Methylpiperazin-l-yl)-N-{5-[7-(6-methylpyridin-2-yl)-4-oxoquinazolin
(trifluoromethoxy)phenyl}cyclopropanecarboxamide
Figure imgf000158_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (80.0 mg, 57% purity, 74.3 μηιοΐ), 2-bromo-6-methylpyridine (17.3 mg, 100 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (6.07 mg, 7.43 μηιοΐ) and potassium carbonate (20.5 mg, 149 μηιοΐ) in N,N-dimethylformamide (66 μΐ), water (260 μΐ) and 1,2-dimethoxyethane (360 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 21.0 mg (48 % yield) of the desired compound.
LC-MS (Method 6): Rt = 1.27 min; MS (ESIneg): m/z = 577 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.90), -0.020 (1.20), -0.008 (16.00), 0.008 (14.52), 0.016 (1.11), 0.018 (0.87), 0.146 (1.77), 1.109 (0.91), 1.122 (2.47), 1.130 (2.85), 1.140 (1.36), 1.241 (1.32), 1.251 (2.85), 1.258 (2.27), 1.271 (0.99), 2.201 (4.95), 2.323 (1.03), 2.327 (1.32), 2.366 (1.57), 2.464 (3.79), 2.518 (5.53), 2.523 (4.12), 2.602 (13.24), 2.670 (1.28), 2.710 (1.36), 7.332 (1.90), 7.351 (2.06), 7.422 (1.36), 7.429 (1.40), 7.444 (1.53), 7.451 (1.57), 7.695 (1.20), 7.698 (1.28), 7.716 (1.07), 7.842 (1.32), 7.861 (2.60), 7.880 (1.57), 7.996 (2.10), 8.016 (1.61), 8.277 (1.53), 8.298 (3.46), 8.325 (2.06), 8.329 (2.23), 8.346 (0.91), 8.350 (1.11), 8.413 (8.78), 8.622 (1.28), 10.661 (1.28).
Example 35
N-{5-[7-(2-methylphenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(4- methylpiperazin- 1 -yl)cyclopropanecarboxamide
Figure imgf000158_0002
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (100 mg, 53% purity, 86.4 μηιοΐ), l-bromo-2-methylbenzene (19.9 mg, 117 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (3.53 mg, 4.32 μηιοΐ) and potassium carbonate (23.9 mg, 173 μηιοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2-dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 26.0 mg (52 % yield) of the title compound.
LC-MS (Method 2): Rt = 0.83 min; MS (ESIpos): m/z = 578 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.80), -0.008 (15.32), 0.008 (16.00), 0.146 (1.92), 1.126 (2.59), 1.134 (3.15), 1.144 (1.58), 1.243 (1.35), 1.253 (3.04), 2.198 (11.61), 2.282 (15.10), 2.327 (2.70), 2.332 (2.14), 2.366 (2.93), 2.463 (4.62), 2.523 (8.11), 2.670 (2.82), 2.710 (2.70), 7.318 (2.82), 7.333 (1.69), 7.356 (2.37), 7.363 (3.15), 7.369 (2.59), 7.409 (1.46), 7.416 (1.46), 7.431 (1.69), 7.438 (1.80), 7.578 (1.58), 7.582 (1.58), 7.599 (1.69), 7.603 (1.69), 7.671 (2.70), 7.702 (1.24), 7.720 (1.13), 8.236 (2.82), 8.257 (2.59), 8.402 (6.08), 8.625 (2.70), 8.632 (2.70), 10.667 (2.70).
Example 36
l-(4-Methylpiperazin-l-yl)-N-{5-[7-(4-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropanecarboxamide
Figure imgf000159_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (100 mg, 53% purity, 86.4 μηιοΐ), 3-bromo-4-methylpyridine (20.1 mg, 117 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (3.53 mg, 4.32 μηιοΐ) and potassium carbonate (23.9 mg, 173 μηιοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2-dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 87: 13. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 25.0 mg (97 % purity, 49 % yield) of the desired compound.
LC-MS (Method 1): Rt = 0.55 min; MS (ESIneg): m/z = 577 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.38), 0.008 (2.31), 1.114 (1.15), 1.126 (3.07), 1.134 (3.55), 1.144 (1.73), 1.244 (1.62), 1.254 (3.55), 1.261 (2.85), 1.274 (1.18), 2.198 (13.51), 2.320 (16.00), 2.366 (0.64), 2.523 (1.60), 2.670 (0.55), 2.710 (0.45), 7.406 (2.44), 7.412 (2.33), 7.418 (4.20), 7.434 (2.05), 7.441 (2.13), 7.637 (1.91), 7.641 (1.98), 7.658 (1.98), 7.662 (2.16), 7.701 (1.53), 7.704 (1.60), 7.722 (1.42), 7.726 (1.29), 7.768 (3.51), 7.772 (3.42), 8.268 (3.35), 8.288 (3.13), 8.423 (7.49), 8.483 (5.55), 8.505 (3.44), 8.518 (3.31), 8.631 (3.51), 8.638 (3.51), 10.668 (3.27). Example 37
N-{5-[7-(6-Aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(4- methylpiperazin- 1 -yl)cyclopropanecarboxamide
Figure imgf000160_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (100 mg, 53% purity, 86.4 μηιοΐ), 5-bromopyridin-2-amine (20.2 mg, 117 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (3.53 mg, 4.32 μηιοΐ) and potassium carbonate (23.9 mg, 173 μηιοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2-dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2%> ammonia) to deliver 16.0 mg (32 % yield) of the desired compound.
LC-MS (Method 1): Rt = 0.48 min; MS (ESIneg): m/z = 578 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (6.22), 0.008 (4.13), 0.146 (0.46), 1.108 (1.55), 1.120 (3.83), 1.128 (4.19), 1.138 (2.01), 1.239 (2.09), 1.249 (4.25), 1.256 (3.46), 1.269 (1.42), 2.196 (16.00), 2.328 (1.17), 2.332 (1.00), 2.366 (1.45), 2.458 (9.07), 2.524 (5.30), 2.670 (0.88), 2.710 (0.57), 6.309 (7.60), 6.566 (3.31), 6.588 (3.25), 7.397 (2.32), 7.403 (2.26), 7.419 (2.41), 7.425 (2.49), 7.683 (1.93), 7.687 (2.03), 7.705 (1.74), 7.709 (1.61), 7.847 (2.12), 7.851 (2.33), 7.868 (2.28), 7.872 (2.72), 7.898 (2.41), 7.909 (5.01), 7.913 (4.33), 7.920 (2.24), 7.926 (2.05), 8.170 (4.15), 8.191 (3.52), 8.366 (9.17), 8.463 (3.56), 8.468 (3.43), 8.603 (4.33), 8.609 (4.25), 10.657 (3.94).
Example 38
N-{5-[7-(2-Fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(4- methylpiperazin-l -yl)propanamide (enantiomer 1)
Figure imgf000161_0001
Enantiomer separation of 130 mg of N- {5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(4-methylpiperazin-l -yl)propanamide (racemate) gave 46 mg of enantiomer 2 (chiral HPLC: Rt = 10.05min) and 44 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 8.40 min; 99% ee.
Separating method: column: YMC Chiralart Cellulose, 5 μιη 250 mm x 21.1 mm; mobile phase: n- heptane 55%/isopropanol 45% with 0.2% diethylamine in the isopropanol phase; temperature: 45°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Cellulose SB 5 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%/isopropanol 50% with 0.2% diethylamine in the isopropanol phase; flow rate: 1 ml/min; temperature: 40°C; UV detection: 235 nm.
LC-MS (Method 7): Rt = 1.87 min; MS (ESIpos): m/z = 570 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.15), 0.008 (1.52), 1.183 (8.34), 1.201 (8.53), 2.182 (16.00), 2.328 (0.62), 2.367 (0.91), 2.403 (1.12), 3.402 (0.67), 3.420 (2.36), 3.437 (2.31), 3.455 (0.64), 7.369 (1.00), 7.372 (1.27), 7.382 (1.19), 7.391 (2.70), 7.403 (1.79), 7.407 (2.79), 7.423 (2.21), 7.429 (3.36), 7.445 (2.27), 7.451 (2.38), 7.507 (0.64), 7.511 (0.73), 7.520 (0.74), 7.525 (1.20), 7.531 (1.06), 7.541 (0.95), 7.545 (1.03), 7.550 (0.53), 7.559 (0.44), 7.563 (0.43), 7.674 (1.78), 7.677 (1.91), 7.683 (1.54), 7.687 (1.32), 7.696 (1.82), 7.703 (2.55), 7.708 (2.02), 7.723 (1.02), 7.727 (0.93), 7.787 (2.01), 7.791 (1.26), 7.808 (2.18), 7.812 (1.35), 7.907 (3.65), 8.278 (3.69), 8.299 (3.42), 8.424 (7.96), 8.509 (3.54), 8.516 (3.58), 10.156 (3.60).
Example 39 N-{5-[7-(2-Fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(4- methylpiperazin-l -yl)propanamide (enantiomer 2)
Figure imgf000162_0001
Enantiomer separation of 130 mg of N- {5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(4-methylpiperazin-l -yl)propanamide (racemate) gave 44 mg of enantiomer 1 (chiral HPLC: Rt = 8.40 min) and 46 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 10.05 min; 99% ee.
Separating method: column: YMC Chiralart Cellulose, 5 μιη 250 mm x 21.1 mm; mobile phase: n- heptane 55%/isopropanol 45% with 0.2% diethylamine in the isopropanol phase; temperature: 45°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Cellulose SB 5 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%/isopropanol 50% with 0.2% diethylamine in the isopropanol phase; flow rate: 1 ml/min; temperature: 40°C; UV detection: 235 nm.
LC-MS (Method 7): Rt = 1.87 min; MS (ESIpos): m/z = 570 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.85), 0.008 (1.84), 1.183 (8.34), 1.201 (8.49), 2.182 (16.00), 2.328 (0.79), 2.367 (1.10), 2.407 (1.12), 2.670 (0.58), 2.710 (0.44), 3.402 (0.68), 3.420 (2.36), 3.438 (2.33), 3.455 (0.63), 7.372 (1.26), 7.382 (1.22), 7.391 (2.74), 7.403 (1.83), 7.408 (2.75), 7.423 (2.17), 7.429 (3.33), 7.445 (2.26), 7.451 (2.32), 7.508 (0.66), 7.512 (0.73), 7.525 (1.21), 7.531 (1.07), 7.546 (1.04), 7.559 (0.43), 7.564 (0.44), 7.674 (1.77), 7.678 (1.95), 7.684 (1.54), 7.687 (1.28), 7.696 (1.84), 7.703 (2.51), 7.708 (2.02), 7.724 (0.99), 7.728 (0.91), 7.787 (2.01), 7.808 (2.18), 7.907 (3.82), 8.279 (3.82), 8.299 (3.52), 8.424 (8.20), 8.509 (3.70), 8.516 (3.69), 10.156 (3.57).
Example 40
2-(4-Methylpiperazin-l-yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]propanamide (enantiomer 1)
Figure imgf000163_0001
Enantiomer separation of 87 mg of 2-(4-methylpiperazin-l -yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)- yl)-2-(trifluoromethoxy)phenyl]propanamide (Racemate) gave 36 mg of enantiomer 2 (chiral HPLC: Rt = 10.20 min) and 37 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 8.97 min; 99% ee. Separating method: column: YMC Chiralart Cellulose, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 65%/ethanol 35% with 0.2%> diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Chiralart Amylose SB 5 μιη, 50 mm x 4.6 mm; mobile phase: iso-hexane 50%)/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 40°C; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m z = 552 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.62), 0.008 (2.75), 1.183 (8.74), 1.200 (8.89), 2.182 (16.00), 2.328 (0.66), 2.366 (1.1 1), 2.404 (1.16), 2.565 (3.46), 2.670 (0.44), 2.710 (0.48), 3.402 (0.75), 3.419 (2.49), 3.437 (2.43), 3.454 (0.68), 7.424 (2.08), 7.430 (2.06), 7.446 (2.36), 7.452 (2.44), 7.464 (0.81), 7.482 (2.51), 7.501 (2.00), 7.537 (3.27), 7.556 (4.84), 7.574 (2.04), 7.671 (1.83), 7.674 (1.89), 7.693 (1.60), 7.696 (1.51), 7.854 (4.69), 7.872 (4.32), 7.875 (3.17), 7.928 (2.03), 7.933 (2.22), 7.949 (2.21), 7.954 (2.52), 8.015 (4.12), 8.019 (3.81), 8.264 (3.88), 8.284 (3.41), 8.417 (8.17), 8.504 (3.52), 8.510 (3.50), 10.154 (3.78).
Example 41
2-(4-Methylpiperazin- 1 -yl)-N-[5-(4-oxo-7-phenylquinazolin
(trifluoromethoxy)phenyl]propanamide (enantiomer 2)
Figure imgf000163_0002
Enantiomer separation of 87 mg of 2-(4-methylpiperazin-l -yl)-N-[5-(4-oxo-7-phenylquinazolin-3(4H)- yl)-2-(trifluoromethoxy)phenyl]propanamide (racemate) gave 37 mg of enantiomer 1 (chiral HPLC: Rt = 8.97 min) and 36 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 10.20 min; 98.6% ee.
Separating method: column: YMC Chiralart Cellulose, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 65%/ethanol 35% with 0.2% diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Chiralart Amylose SB 5 μιη, 50 mm x 4.6 mm; mobile phase: iso-hexane 50%/ethanol 50% with 0.2% diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 40°C; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 552 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.47), 0.008 (2.78), 1.183 (10.35), 1.201 (10.59), 2.184 (16.00), 2.328 (0.95), 2.366 (1.32), 2.407 (1.36), 2.670 (0.71), 2.710 (0.59), 3.402 (0.86), 3.420 (2.94), 3.438 (2.85), 3.455 (0.79), 7.424 (2.51), 7.431 (2.47), 7.446 (2.87), 7.453 (2.98), 7.464 (1.03), 7.483 (3.14), 7.501 (2.51), 7.537 (4.05), 7.557 (5.97), 7.575 (2.46), 7.671 (2.26), 7.675 (2.37), 7.693 (1.96), 7.697 (1.84), 7.854 (5.77), 7.872 (5.28), 7.876 (3.96), 7.929 (2.46), 7.933 (2.74), 7.950 (2.71), 7.954 (3.14), 8.015 (5.15), 8.019 (4.85), 8.264 (4.92), 8.285 (4.30), 8.417 (10.43), 8.503 (4.25), 8.509 (4.26), 10.154 (4.48).
Example 42
N-{5-[7-(5-Fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin-1 -yl)propanamide (racemate)
Figure imgf000164_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (Racemate) (100 mg, 60% purity, 99.8 μιηοΐ), 3-bromo-5-fluoropyridine (23.7 mg, 135 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.15 mg, 9.98 μιηοΐ) and potassium carbonate (27.6 mg, 200 μιηοΐ) in N,N-dimethylformamide (88 μΐ), water (350 μΐ) and 1,2-dimethoxyethane (480 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 30.0 mg (53 % yield) of the desired compound.
LC-MS (Method 6): Rt = 1.15 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.16), 1.182 (8.38), 1.200 (8.51), 2.182 (16.00), 2.328 (0.65), 2.404 (1.16), 2.565 (3.39), 2.670 (0.41), 3.402 (0.69), 3.420 (2.35), 3.438 (2.31), 3.455 (0.65), 7.429 (1.87), 7.436 (1.91), 7.451 (2.16), 7.457 (2.25), 7.675 (1.72), 7.678 (1.81), 7.696 (1.52), 7.700 (1.43), 8.035 (1.80), 8.039 (1.87), 8.055 (2.06), 8.060 (2.22), 8.199 (3.67), 8.203 (3.60), 8.291 (3.45), 8.297 (1.35), 8.303 (1.77), 8.311 (3.22), 8.323 (1.11), 8.329 (1.60), 8.334 (1.13), 8.446 (7.45), 8.513 (3.52), 8.519 (3.56), 8.685 (3.03), 8.692 (2.99), 8.993 (3.66), 10.156 (3.67).
Example 43
N-{5-[7-(5-Chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin- 1 -yl)propanamide (racemate)
Figure imgf000165_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 99.8 μηιοΐ), 3-bromo-5-chloropyridine (25.9 mg, 135 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.15 mg, 9.98 μηιοΐ) and potassium carbonate (27.6 mg, 200 μηιοΐ) in N,N-dimethylformamide (88 μΐ), water (350 μΐ) and 1,2-dimethoxyethane (480 μΐ) was degassed by passing argon through it for 5 min and then heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0,2%> ammonia) to deliver 35.0 mg (60 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.27 min; MS (ESIpos): m/z = 587 [M+H]+ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.48), -0.008 (3.49), 0.008 (3.37), 0.146 (0.45), 1.182 (8.36), 1.200 (8.51), 2.182 (16.00), 2.327 (1.26), 2.366 (0.93), 2.399 (1.05), 2.670 (1.11), 2.674 (0.87), 3.403 (0.72), 3.420 (2.41), 3.438 (2.35), 3.455 (0.69), 7.429 (1.95), 7.435 (1.86), 7.451 (2.14), 7.457 (2.23), 7.675 (1.65), 7.679 (1.71), 7.697 (1.44), 7.701 (1.35), 8.032 (1.95), 8.037 (2.02), 8.053 (2.17), 8.057 (2.38), 8.198 (3.79), 8.202 (3.67), 8.288 (3.73), 8.309 (3.19), 8.446 (8.03), 8.478 (2.35), 8.483 (4.27), 8.489 (2.47), 8.511 (3.43), 8.517 (3.40), 8.729 (2.71), 8.735 (2.59), 9.055 (4.00), 9.060 (3.97), 10.156 (3.46).
Example 44
N-{5-[7-(3-Fluoropyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin- 1 -yl)propanamide (racemate)
Figure imgf000166_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 99.8 μηιοΐ), 4-bromo-3-fluoropyridine (23.7 mg, 135 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.15 mg, 9.98 μηιοΐ) and potassium carbonate (27.6 mg, 200 μηιοΐ) in N,N-dimethylformamide (88 μΐ), water (350 μΐ) and 1,2-dimethoxyethane (480 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 36.0 mg (63 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.12 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (6.85), 0.008 (4.34), 0.146 (0.52), 1.183 (8.54), 1.200 (8.52), 2.181 (16.00), 2.328 (1.00), 2.399 (1.25), 2.564 (3.51), 2.670 (0.71), 3.402 (0.79), 3.420 (2.46), 3.438 (2.38), 3.455 (0.66), 7.428 (2.14), 7.434 (2.08), 7.449 (2.35), 7.456 (2.35), 7.678 (1.92), 7.681 (1.84), 7.699 (1.62), 7.703 (1.43), 7.791 (1.76), 7.804 (2.04), 7.808 (1.87), 7.821 (1.72), 7.875 (2.03), 7.895 (2.21), 8.039 (3.70), 8.328 (3.73), 8.349 (3.38), 8.454 (8.29), 8.516 (3.80), 8.522 (3.66), 8.593 (2.78), 8.605 (2.60), 8.757 (3.71), 8.763 (3.51), 10.157 (3.56). Example 45
N-{5-[7-(3-Fluoropyridin-2-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin-1 -yl)propanamide (racemate)
Figure imgf000167_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 60% purity, 99.8 μπιοΐ), 2-bromo-3-fluoropyridine (23.7 mg, 135 μπιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (8.15 mg, 9.98 μπιοΐ) and potassium carbonate (27.6 mg, 200 μιηοΐ) in N,N-dimethylformamide (88 μΐ), water (350 μΐ) and 1,2-dimethoxyethane (480 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 34.0 mg (60 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.19 min; MS (ESIneg): m/z = 569 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.86), 0.008 (2.80), 1.183 (8.39), 1.201 (8.49), 2.182 (16.00), 2.328 (0.69), 2.333 (0.63), 2.407 (1.10), 2.566 (3.14), 2.670 (0.45), 3.401 (0.70), 3.419 (2.39), 3.437 (2.32), 3.454 (0.66), 7.435 (1.95), 7.442 (1.94), 7.457 (2.18), 7.464 (2.27), 7.590 (0.95), 7.601 (1.51), 7.611 (2.14), 7.622 (1.83), 7.632 (1.22), 7.676 (1.70), 7.680 (1.79), 7.698 (1.50), 7.701 (1.42), 7.922 (1.21), 7.925 (1.29), 7.943 (1.15), 7.946 (1.21), 7.951 (1.29), 7.954 (1.31), 7.972 (1.10), 7.975 (1.14), 8.151 (1.83), 8.155 (1.24), 8.172 (2.33), 8.253 (3.39), 8.328 (3.93), 8.349 (3.17), 8.435 (8.10), 8.514 (3.53), 8.521 (3.57), 8.645 (1.13), 8.649 (1.75), 8.653 (1.43), 8.656 (1.37), 8.660 (1.76), 8.664 (1.26), 10.156 (3.44).
Example 46
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(4-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (enantiomer 1)
Figure imgf000168_0001
Enantiomer separation of 93 mg of 2-(4-methylpiperazin-l-yl)-N-{5-[7-(4-methylpyridin-3-yl)-4- oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) gave 40 mg of enantiomer 2 (chiral HPLC: Rt = 10.99 min) and 40 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 7.65 min; 100% ee.
Separating method: column: Kromasil 5-CelluCoat, 250 mm x 21.2 mm; mobile phase: n-heptane 50%/ethanol 50% with 0.2%> diethylamine in the ethanol phase; temperature: rt; flow rate: 25 ml/min; UV detection: 230 nm.
Analysis: column: Phenomenex Cellulose-1 3 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%o/ethanol 50%> with 0.2%> diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 30°C; UV detection: 220 nm.
LC-MS (Method 1): Rt = 0.56 min; MS (ESIneg): m/z = 565 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.83), 0.008 (2.97), 1.187 (7.25), 1.205 (7.42), 1.235 (0.91), 2.211 (3.33), 2.323 (16.00), 2.366 (0.82), 2.670 (0.62), 2.710 (0.55), 3.413 (0.56), 3.431 (1.64), 3.448 (1.62), 3.466 (0.53), 7.409 (2.03), 7.422 (2.16), 7.430 (1.73), 7.437 (1.59), 7.452 (1.79), 7.458 (1.86), 7.641 (1.78), 7.645 (1.93), 7.662 (1.89), 7.666 (2.18), 7.677 (1.64), 7.680 (1.69), 7.699 (1.37), 7.702 (1.34), 7.773 (3.37), 7.776 (3.38), 8.275 (3.20), 8.295 (3.00), 8.431 (6.88), 8.487 (2.71), 8.504 (2.29), 8.521 (1.61), 10.149 (2.58).
Example 47
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(5-methylpyridin-3-yl)-4-oxoquinazolin
(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000168_0002
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (340 mg, 53% purity, 300 μηιοΐ), 3-bromo-5-methylpyridine (69.6 mg, 404 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (12.2 mg, 15.0 μηιοΐ) and potassium carbonate (82.8 mg, 599 μηιοΐ) in N,N-dimethylformamide (270 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.5 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 92.0 mg (54 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.59 min; MS (ESIpos): m/z = 567 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (1.36), 1.183 (7.96), 1.200 (7.89), 2.182 (14.89), 2.328 (0.69), 2.367 (1.11), 2.421 (16.00), 2.670 (0.46), 2.710 (0.42), 3.402 (0.72), 3.420 (2.27), 3.437 (2.17), 3.455 (0.64), 7.427 (1.83), 7.433 (1.80), 7.449 (2.08), 7.455 (2.05), 7.673 (1.73), 7.676 (1.73), 7.695 (1.47), 7.974 (1.88), 7.979 (1.91), 7.995 (2.03), 8.000 (2.13), 8.100 (3.96), 8.105 (3.67), 8.122 (2.96), 8.281 (3.57), 8.302 (3.07), 8.432 (7.18), 8.508 (3.89), 8.514 (6.02), 8.870 (3.11), 8.876 (2.93), 10.155 (3.47).
Example 48
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(5-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (enantiomer 1)
Figure imgf000169_0001
Enantiomer separation of 92 mg of 2-(4-methylpiperazin-l-yl)-N-{5-[7-(5-methylpyridin-3-yl)-4- oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) gave 43 mg of enantiomer 2 (chiral HPLC: Rt = 10.13 min) and 40 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 8.77 min; 99% ee.
Separating method: column: YMC Chiralart Cellulose SB 5 μηι, 250 mm x 20mm; mobile phase: n- heptane 35%>/ethanol 65%> with 0.2%> diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 220 nm. Analysis: column: YMC Chiralart Amylose SB, 5 μηι, 250 mm x 4.6 mm; mobile phase: n-heptane 30%/ethanol 70% with 0.2% diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 50°C; UV detection: 265 nm.
LC-MS (Method 1): Rt = 0.60 min; MS (ESIneg): m/z = 565 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.53), 0.008 (1.59), 1.183 (7.91), 1.200 (8.04), 2.182 (15.13), 2.328 (0.66), 2.366 (1.01), 2.421 (16.00), 2.523 (1.63), 2.670 (0.45), 2.710 (0.42), 3.402 (0.66), 3.420 (2.22), 3.437 (2.17), 3.455 (0.62), 7.427 (1.75), 7.433 (1.75), 7.449 (2.02), 7.455 (2.08), 7.673 (1.63), 7.676 (1.70), 7.695 (1.42), 7.698 (1.35), 7.974 (1.74), 7.978 (1.86), 7.995 (1.94), 7.999 (2.15), 8.101 (3.70), 8.105 (3.59), 8.123 (2.93), 8.281 (3.42), 8.302 (2.99), 8.432 (7.13), 8.508 (3.93), 8.514 (5.79), 8.872 (2.45), 10.155 (3.56).
Example 49
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(5-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (enantiomer 2)
Figure imgf000170_0001
Enantiomer separation of 92 mg of 2-(4-methylpiperazin-l-yl)-N-{5-[7-(5-methylpyridin-3-yl)-4- oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) gave 40 mg of enantiomer 1 (chiral HPLC: Rt = 8.77 min) and 43 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 10.13 min; 98.8% ee.
Separating method: column: YMC Chiralart Cellulose SB 5 μιη, 250 mm x 20mm; mobile phase: n- heptane 35%>/ethanol 65%> with 0.2%> diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 220 nm.
Analysis: column: YMC Chiralart Amylose SB, 5 μιη, 250 mm x 4.6 mm; mobile phase: n-heptane 30%o/ethanol 70%> with 0.2%> diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 50°C; UV detection: 265 nm.
LC-MS (Method 1): Rt = 0.61 min; MS (ESIneg): m/z = 565 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.52), 0.008 (1.47), 1.183 (8.14), 1.200 (8.26), 2.182 (15.51), 2.328 (0.63), 2.366 (1.19), 2.421 (16.00), 2.524 (1.68), 2.562 (3.32), 2.670 (0.43), 2.710 (0.59), 3.402 (0.68), 3.420 (2.33), 3.437 (2.27), 3.455 (0.64), 7.427 (1.85), 7.433 (1.83), 7.449 (2.10), 7.455 (2.17), 7.673 (1.68), 7.676 (1.72), 7.695 (1.47), 7.698 (1.37), 7.974 (1.84), 7.978 (1.92), 7.995 (2.03), 7.999 (2.22), 8.100 (3.78), 8.104 (3.63), 8.123 (2.89), 8.281 (3.58), 8.302 (3.13), 8.432 (7.34), 8.508 (4.11), 8.514 (4.47), 8.873 (1.19), 10.155 (3.60).
Example 50
N-{5-[7-(6-Aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin-1 -yl)propanamide (racemate)
Figure imgf000171_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (45.0 mg, 55% purity, 41.2 μιηοΐ), 5-bromopyridin-2-amine (9.61 mg, 55.6 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (1.68 mg, 2.06 μιηοΐ) and potassium carbonate (11.4 mg, 82.3 μιηοΐ) in N,N-dimethylformamide (37 μΐ), water (150 μΐ) and 1,2-dimethoxyethane (200 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 95°C for 2 h. After cooling to rt, the reaction mixture was treated with 2 mL of dichloromethane/methanol 9:1 and 0.5 mL of an aqueous sodium chloride solution. After phase separation, the aqueous layer was repeatedly extracted with dichloromethane/methanol 9: 1. The combined organics were evaporated and the residue was purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% of formic acid) to deliver 9.00 mg (97 % purity, 37 % yield) of the desired compound.
LC-MS (Method 6): Rt = 0.75 min; MS (ESIneg): m/z = 566 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.149 (0.46), 0.146 (0.45), 1.180 (8.40), 1.197 (8.45), 2.181 (16.00), 2.328 (0.81), 2.366 (1.29), 2.402 (1.41), 2.670 (0.53), 2.710 (0.43), 3.398 (1.10), 3.416 (2.59), 3.433 (2.45), 3.451 (0.80), 6.312 (7.16), 6.568 (2.89), 6.590 (2.93), 7.410 (1.76), 7.417 (1.77), 7.432 (2.02), 7.438 (2.08), 7.660 (1.77), 7.681 (1.59), 7.851 (1.85), 7.855 (1.99), 7.872 (2.04), 7.876 (2.32), 7.901 (1.94), 7.913 (4.45), 7.917 (3.98), 7.929 (1.87), 8.177 (3.38), 8.197 (2.93), 8.373 (6.88), 8.465 (3.25), 8.471 (3.25), 8.484 (3.43), 8.491 (3.34), 10.147 (3.79).
Example 51
N-{5-[7-(6-Aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin-l -yl)propanamide (enantiomer 1)
Figure imgf000172_0001
Enantiomer separation of 84 mg of N- {5-[7-(6-aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(4-methylpiperazin-l -yl)propanamide (Racemate) gave 37 mg of enantiomer 2 (chiral HPLC: Rt = 10.92 min) and 37 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 9.32 min; 99% ee.
Separating method: column: Daicel Chiralcel OX-H 5 μιη, 250 mm x 20mm; mobile phase: n-heptane 30%/ethanol 70% with 0.2% diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 235 nm.
Analysis: column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 4.6 mm; mobile phase: iso-hexane 30%/ethanol 70% with 0.2% diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 50°C; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.46 min; MS (ESIneg): m/z = 566 [M-H]"
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : -0.007 (1.22), 0.006 (0.83), 1.181 (8.65), 1.196 (8.60), 1.406 (0.45), 2.181 (16.00), 2.362 (0.76), 2.401 (0.78), 2.565 (2.59), 3.402 (0.73), 3.416 (2.48), 3.430 (2.39), 3.444 (0.65), 6.311 (6.85), 6.571 (2.92), 6.589 (2.85), 7.413 (2.16), 7.418 (2.08), 7.430 (2.27), 7.436 (2.30), 7.661 (1.78), 7.664 (1.79), 7.679 (1.59), 7.681 (1.42), 7.853 (1.98), 7.856 (2.11), 7.870 (2.06), 7.873 (2.32), 7.903 (2.16), 7.909 (2.48), 7.913 (4.54), 7.916 (4.00), 7.921 (2.11), 7.926 (1.93), 8.178 (4.08), 8.195 (3.52), 8.373 (8.98), 8.467 (2.76), 8.471 (2.69), 8.486 (3.99), 8.492 (3.85), 10.146 (3.62).
Example 52
N-{5-[7-(6-Aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(4- methylpiperazin-l -yl)propanamide (enantiomer 2)
Figure imgf000172_0002
Enantiomer separation of 84 mg of N- {5-[7-(6-aminopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(4-methylpiperazin-l -yl)propanamide (Racemate) gave 37 mg of enantiomer 1 (chiral HPLC: Rt = 9.32 min) and 37 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 10.92 min; 99% ee.
Separating method: column: Daicel Chiralcel OX-H 5 μηι, 250 mm x 20mm; mobile phase: n-heptane 30%/ethanol 70% with 0.2% diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 235 nm.
Analysis: column: Daicel Chiralcel OX-H, 5 μηι, 250 mm x 4.6 mm; mobile phase: iso-hexane 30%/ethanol 70% with 0.2% diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: 50°C; UV detection: 235 nm.
LC-MS (Method 1): Rt = 0.48 min; MS (ESIneg): m/z = 566 [M-H]"
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : -0.006 (1.71), 0.006 (1.30), 1.182 (8.54), 1.196 (8.51), 1.234 (0.51), 2.181 (16.00), 2.362 (0.82), 2.406 (0.79), 2.565 (2.62), 2.636 (0.42), 3.403 (0.73), 3.417 (2.47), 3.431 (2.40), 3.445 (0.69), 6.311 (6.77), 6.571 (2.80), 6.588 (2.74), 7.413 (2.14), 7.418 (2.07), 7.430 (2.25), 7.436 (2.27), 7.661 (1.74), 7.664 (1.80), 7.679 (1.60), 7.682 (1.43), 7.853 (1.95), 7.857 (2.10), 7.870 (2.01), 7.874 (2.31), 7.903 (2.11), 7.909 (2.43), 7.913 (4.48), 7.916 (4.01), 7.921 (2.13), 7.926 (1.93), 8.178 (4.00), 8.195 (3.47), 8.373 (8.95), 8.467 (2.64), 8.471 (2.59), 8.486 (3.96), 8.491 (3.88), 10.146 (3.61).
Example 53
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(l -methyl-lH-pyrazol-4-yl)-4-oxoquinazolin
(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000173_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (120 mg, 65% purity, 130 μηιοΐ), 4-bromo-l -methyl- lH-pyrazole (28.2 mg, 175 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (10.6 mg, 13.0 μηιοΐ) and potassium carbonate (35.8 mg, 259 μηιοΐ) in N,N-dimethylformamide (120 μΐ), water (460 μΐ) and 1,2-dimethoxyethane (630 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 24.0 mg (33 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.14 min; MS (ESIpos): m/z = 556 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.006 (2.26), 0.006 (1.47), 1.180 (7.17), 1.194 (7.14), 2.179 (13.66), 2.362 (0.79), 2.400 (0.70), 2.447 (0.62), 2.519 (1.35), 2.522 (1.20), 2.562 (2.30), 3.401 (0.60), 3.415 (2.01), 3.429 (1.96), 3.442 (0.55), 3.906 (16.00), 7.407 (1.65), 7.412 (1.63), 7.425 (1.81), 7.430 (1.82), 7.656 (1.51), 7.658 (1.54), 7.673 (1.35), 7.816 (1.68), 7.819 (1.72), 7.832 (1.77), 7.835 (1.88), 7.928 (3.53), 7.931 (3.32), 8.114 (5.50), 8.141 (3.35), 8.158 (2.91), 8.354 (6.88), 8.430 (5.04), 8.476 (3.16), 8.481 (3.12), 10.142 (3.14).
Example 54
N-{5-[7-(2-Aminopyrimidin-5-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(4- methylpiperazin-1 -yl)propanamide (racemate)
Figure imgf000174_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (120 mg, 65% purity, 130 μιηοΐ), 5-bromopyrimidin-2-amine (30.5 mg, 176 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (5.31 mg, 6.50 μιηοΐ) and potassium carbonate (35.9 mg, 260 μιηοΐ) in N,N-dimethylformamide (120 μΐ), water (460 μΐ) and 1,2-dimethoxyethane (630 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. After cooling down to rt, the reaction mixture was partitioned between 4 mL ethyl acetate and 1 mL of an aqueous solution of 50% water and 50% brine. Extractive work-up was performed with ethyl acetate and dichloromethane. The combined organic extracts were evaporated and the residue was purified with silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. This delivered 25.0 mg (98 % purity, 33 % yield) of the title compound.
LC-MS (Method 6): Rt = 0.92 min; MS (ESIneg): m/z = 567 [M-H] Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.47), -0.008 (4.82), 0.146 (0.48), 1.180 (8.83), 1.198 (8.96), 1.908 (0.56), 2.184 (13.69), 2.328 (0.83), 2.366 (1.24), 2.405 (1.33), 2.670 (0.60), 2.710 (0.50), 3.400 (0.79), 3.417 (2.50), 3.435 (2.43), 3.453 (0.72), 7.005 (8.21), 7.415 (1.88), 7.421 (1.90), 7.437 (2.18), 7.443 (2.29), 7.666 (1.93), 7.684 (1.69), 7.899 (1.99), 7.903 (2.03), 7.920 (2.19), 7.924 (2.35), 8.015 (4.27), 8.019 (3.97), 8.201 (3.87), 8.222 (3.24), 8.392 (7.77), 8.488 (3.27), 8.494 (3.23), 8.796 (16.00), 10.147 (3.93).
Example 55
2-(4-Methylpiperazin-l-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000175_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (120 mg, 65% purity, 130 μιηοΐ), 3-bromopyridine (19 μΐ, 180 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium- dichloromethane -complex (5.31 mg, 6.50 μιηοΐ) and potassium carbonate (35.9 mg, 260 μιηοΐ) ίη Ν,Ν- dimethylformamide (120 μΐ), water (460 μΐ) and 1,2-dimethoxyethane (630 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for 2 h. After cooling down to rt, the reaction mixture was partitioned between 4 mL ethyl acetate and 1 mL water. Extractive work -up was performed with ethyl acetate and the combined organic layers were evaporated. The residue was submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.1%> formic acid) to deliver 54.0 mg (97 % purity, 73 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.01 min; MS (ESIneg): m/z = 551 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.50), 0.008 (2.33), 1.183 (8.34), 1.200 (8.39), 2.182 (16.00), 2.328 (0.63), 2.367 (1.04), 2.402 (1.21), 2.524 (1.63), 3.402 (0.84), 3.420 (2.39), 3.438 (2.30), 3.455 (0.66), 7.428 (1.98), 7.435 (1.98), 7.450 (2.18), 7.457 (2.26), 7.558 (1.49), 7.569 (1.56), 7.577 (1.56), 7.589 (1.57), 7.674 (1.78), 7.677 (1.80), 7.696 (1.51), 7.699 (1.40), 7.987 (1.88), 7.991 (1.96), 8.008 (2.10), 8.012 (2.26), 8.118 (3.85), 8.122 (3.62), 8.275 (1.22), 8.280 (1.82), 8.284 (1.59), 8.291 (4.01), 8.300 (1.78), 8.304 (1.31), 8.312 (3.21), 8.438 (7.69), 8.511 (3.51), 8.517 (3.48), 8.669 (2.15), 8.673 (2.10), 8.681 (2.13), 8.685 (2.02), 9.077 (3.05), 9.083 (3.05), 10.156 (3.65). Example 56
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(6-methylpyridin-2-yl)-4-oxoquinazolin
(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000176_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (285 mg, 64% purity, 303 μηιοΐ), 2-bromo-6-methylpyridine (70.4 mg, 409 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (24.8 mg, 30.3 μηιοΐ) and potassium carbonate (83.8 mg, 607 μηιοΐ) in N,N-dimethylformamide (270 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.5 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 87: 13. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 100 mg (58 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.20 min; MS (ESIneg): m/z = 565 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 1.182 (7.14), 1.200 (7.26), 2.182 (13.67), 2.328 (0.66), 2.367 (0.90), 2.406 (1.01), 2.524 (1.81), 2.565 (2.99), 2.605 (16.00), 2.670 (0.43), 3.401 (0.61), 3.418 (2.04), 3.436 (1.97), 3.453 (0.56), 7.333 (2.34), 7.353 (2.53), 7.434 (1.67), 7.441 (1.67), 7.456 (1.92), 7.463 (2.00), 7.671 (1.55), 7.674 (1.64), 7.693 (1.34), 7.696 (1.29), 7.844 (1.50), 7.863 (3.00), 7.882 (1.73), 7.999 (2.54), 8.018 (1.92), 8.283 (1.76), 8.304 (4.20), 8.329 (2.52), 8.332 (2.70), 8.350 (0.96), 8.353 (1.18), 8.420 (10.22), 8.505 (3.12), 8.512 (3.17), 10.153 (3.23).
Example 57
N-{5-[7-(5-Chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (enantiomer 1)
Figure imgf000177_0001
Enantiomer separation of 220 mg of N- {5-[7-(5-chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(morpholin-4-yl)propanamide (racemate) gave 85 mg of enantiomer 2 (chiral HPLC: Rt = 16.40 min) and 85 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 12.98 min; 99% ee.
Separating method: column: Daicel Chiralpak IB 5 μιη, 250 mm x 20mm; mobile phase: n-heptane 35%/ethanol 65% with 0.2%> diethylamine in the ethanol phase; temperature: 25°C; flow rate: 15 ml/min; UV detection: 210 nm.
Analysis: column: Daicel Chiralpak IB-3, 3 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%>/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: rt; UV detection: 220 nm.
LC-MS (Method 6): Rt = 1.85 min; MS (ESIpos): m/z = 574 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.99), -0.008 (16.00), 0.008 (15.25), 0.147 (1.83), 1.123 (2.96), 1.141 (6.20), 1.159 (3.12), 1.198 (14.22), 1.216 (14.22), 1.356 (1.51), 2.328 (2.91), 2.366 (1.67), 2.567 (7.33), 2.579 (4.20), 2.596 (1.78), 2.670 (3.18), 2.710 (1.83), 2.879 (1.67), 2.896 (1.78), 3.384 (1.29), 3.402 (4.09), 3.420 (3.88), 3.437 (1.08), 3.659 (9.86), 7.448 (3.29), 7.455 (3.07), 7.470 (3.82), 7.477 (3.88), 7.679 (2.96), 7.701 (2.42), 8.032 (3.18), 8.037 (3.12), 8.053 (3.61), 8.057 (3.82), 8.199 (6.57), 8.203 (6.25), 8.289 (6.52), 8.310 (5.66), 8.428 (6.09), 8.434 (6.14), 8.445 (13.79), 8.478 (3.66), 8.484 (7.00), 8.489 (4.09), 8.730 (6.14), 8.735 (5.87), 9.055 (6.52), 9.060 (6.41), 10.099 (5.98).
Example 58
N-{5-[7-(5-Chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (enantiomer 2)
Figure imgf000178_0001
Enantiomer separation of 220 mg of N- {5-[7-(5-chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}-2-(morpholin-4-yl)propanamide (racemate) gave 85 mg of enantiomer 1 (chiral HPLC: Rt = 12.98 min) and 85 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 16.40 min; 99% ee.
Separating method: column: Daicel Chiralpak IB 5 μιη, 250 mm x 20mm; mobile phase: n-heptane 35%/ethanol 65% with 0.2%> diethylamine in the ethanol phase; temperature: 25°C; flow rate: 15 ml/min; UV detection: 210 nm.
Analysis: column: Daicel Chiralpak IB-3, 3 μιη, 50 mm x 4.6 mm; mobile phase: n-heptane 50%>/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; temperature: rt; UV detection: 220 nm.
LC-MS (Method 6): Rt = 1.85 min; MS (ESIpos): m/z = 574 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.97), -0.008 (8.94), 0.008 (8.75), 0.146 (0.91), 1.127 (3.20), 1.145 (6.75), 1.164 (3.61), 1.198 (15.84), 1.216 (16.00), 1.356 (1.91), 2.327 (1.29), 2.366 (0.69), 2.567 (7.56), 2.579 (4.24), 2.597 (1.63), 2.607 (0.97), 2.665 (1.04), 2.670 (1.35), 2.674 (1.04), 2.710 (0.69), 2.871 (0.69), 2.889 (1.98), 2.907 (1.91), 2.925 (0.63), 3.384 (1.35), 3.401 (4.36), 3.419 (4.30), 3.437 (1.19), 3.648 (6.43), 3.659 (11.26), 3.669 (6.46), 7.448 (3.36), 7.455 (3.42), 7.470 (3.95), 7.476 (4.14), 7.675 (3.11), 7.679 (3.33), 7.697 (2.67), 7.701 (2.64), 8.031 (3.45), 8.036 (3.67), 8.052 (3.92), 8.057 (4.36), 8.198 (6.87), 8.202 (6.87), 8.288 (6.65), 8.309 (5.68), 8.428 (6.09), 8.434 (6.27), 8.444 (14.02), 8.477 (4.05), 8.483 (7.59), 8.488 (4.58), 8.729 (5.33), 8.734 (5.27), 9.055 (6.65), 9.059 (6.84), 10.099 (6.56).
Example 59
2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin
(trifluoromethoxy)phenyl}propanamide (enantiomer 1)
Figure imgf000179_0001
Enantiomer separation of 123 mg of 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(pyridin-3- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) gave 53 mg of enantiomer 2 (chiral HPLC: Rt = 16.66 min) and 50 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 13.53 min; 99% ee, 90% purity. The material was then purified by RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 37 mg of the title compound.
Separating method: column: Daicel Chiralcel IB, 5 μιη 250 mm x 30 mm; mobile phase: n-heptane 60%/ethanol 40% with 0.2% diethylamine in the ethanol phase; temperature: 35°C; flow rate: 40 ml/min; UV detection: 220 nm.
Analysis: column: Daicel Chiralpak IB-3 3 μιη, 50 mm x 4.6 mm; mobile phase: heptane 50%/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 220 nm.
LC-MS (Method 1): Rt = 0.85 min; MS (ESIneg): m/z = 564 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.51), 0.008 (2.22), 1.157 (15.76), 1.175 (16.00), 1.804 (4.52), 1.816 (3.14), 1.920 (1.00), 1.943 (3.16), 1.962 (1.87), 1.989 (2.57), 2.014 (0.79), 2.328 (0.59), 2.367 (0.60), 2.524 (1.89), 2.590 (11.05), 2.670 (0.71), 2.710 (0.65), 3.293 (1.71), 3.327 (4.76), 3.344 (1.27), 4.266 (5.30), 7.449 (3.44), 7.456 (3.43), 7.471 (4.03), 7.477 (4.14), 7.559 (2.89), 7.571 (3.03), 7.579 (3.03), 7.591 (3.08), 7.670 (3.19), 7.674 (3.35), 7.692 (2.74), 7.696 (2.58), 7.988 (3.71), 7.992 (3.96), 8.009 (4.14), 8.013 (4.63), 8.119 (7.22), 8.123 (7.01), 8.276 (2.36), 8.282 (3.36), 8.286 (2.98), 8.292 (7.58), 8.302 (3.43), 8.306 (2.70), 8.313 (6.22), 8.436 (14.83), 8.455 (6.83), 8.461 (6.79), 8.669 (3.90), 8.673 (4.03), 8.681 (3.89), 8.685 (3.79), 9.079 (5.72), 9.084 (5.61), 9.725 (7.09).
Example 60
2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(pyridin-3-yl)quinazolin
(trifluoromethoxy)phenyl}propanamide (enantiomer 2)
Figure imgf000180_0001
Enantiomer separation of 123 mg of 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-N-{5-[4-oxo-7-(pyridin-3- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) gave 50 mg of enantiomer 1 (chiral HPLC: Rt = 13.53 min) and 53 mg of the title compound (enantiomer 2): chiral HPLC: Rt = 16.66 min; 99% ee, 90% purity. The material was then purified by RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 39 mg the title compound.
Separating method: column: Daicel Chiralcel IB, 5 μιη 250 mm x 30 mm; mobile phase: n-heptane 60%/ethanol 40% with 0.2% diethylamine in the ethanol phase; temperature: 35°C; flow rate: 40 ml/min; UV detection: 220 nm.
Analysis: column: Daicel Chiralpak IB-3 3 μιη, 50 mm x 4.6 mm; mobile phase: heptane 50%/ethanol 50% with 0.2%) diethylamine in the ethanol phase; flow rate: 1 ml/min; UV detection: 220 nm.
LC-MS (Method 1): Rt = 0.87 min; MS (ESIneg): m/z = 564 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.04), 1.157 (15.84), 1.175 (16.00), 1.803 (4.57), 1.816 (3.15), 1.918 (0.98), 1.943 (3.18), 1.961 (1.92), 1.989 (2.58), 2.013 (0.81), 2.327 (0.52), 2.590 (11.06), 2.670 (0.57), 2.710 (0.42), 3.292 (1.57), 3.327 (4.67), 3.344 (1.24), 4.267 (5.47), 7.449 (3.68), 7.455 (3.64), 7.471 (4.29), 7.477 (4.42), 7.557 (2.99), 7.569 (3.11), 7.577 (3.18), 7.589 (3.21), 7.670 (3.47), 7.674 (3.55), 7.692 (2.91), 7.696 (2.71), 7.987 (3.82), 7.992 (3.94), 8.008 (4.21), 8.012 (4.53), 8.118 (7.87), 8.123 (7.47), 8.275 (2.45), 8.280 (3.60), 8.285 (3.08), 8.291 (8.08), 8.300 (3.60), 8.305 (2.77), 8.312 (6.62), 8.436 (15.97), 8.455 (7.62), 8.462 (7.61), 8.669 (4.49), 8.672 (4.41), 8.681 (4.45), 8.684 (4.24), 9.077 (6.04), 9.083 (6.22), 9.725 (7.11).
Example 61
Methyl 4-{3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromethoxy)phenyl]-4-oxo- 3 ,4-dihydroquinazolin-7-yl} benzoate
Figure imgf000181_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (40.0 mg, 98% purity, 70.8 μηιοΐ), [4-(methoxycarbonyl)phenyl]boronic acid (17.7 mg, 97% purity, 95.6 μηιοΐ), [l ,l -Bis-(Diphenylphosphino)-ferrocen]-Dichloropalladium- Dichloromethane -complex (2.89 mg, 3.54 μηιοΐ) and potassium carbonate (19.6 mg, 142 μηιοΐ) in N,N- dimethylformamide (62 μΐ), water (250 μΐ) and 1 ,2-dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 36.9 mg (86 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 609 [M+H]+
Ή-ΝΜΡν (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.96), 0.008 (0.86), 0.068 (0.59), 1.1 17 (1.23), 1.129 (3.54), 1.137 (3.84), 1.147 (1.76), 1.233 (0.45), 1.272 (1.67), 1.283 (3.82), 1.290 (3.27), 1.303 (1.30), 2.471 (5.49), 2.482 (4.48), 2.523 (0.99), 3.708 (5.39), 3.854 (0.77), 3.904 (16.00), 7.430 (1.83), 7.436 (1.77), 7.452 (2.00), 7.458 (2.05), 7.702 (1.63), 7.706 (1.65), 7.724 ( 1.41), 7.727 (1.32), 7.908 (0.79), 7.982 (1.78), 7.986 (1.89), 8.003 (2.00), 8.007 (2.28), 8.017 (3.81), 8.038 (6.01), 8.101 (9.30), 8.123 (3.58), 8.273 (0.56), 8.288 (3.36), 8.309 (2.87), 8.429 (7.00), 8.575 (3.41), 8.582 (3.38), 10.627 (3.60).
Example 62
Methyl 3- {3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl} amino)-4-(trifluoromethoxy)phenyl]-4- 3 ,4-dihydroquinazolin-7-yl} benzoate
Figure imgf000182_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (40.0 mg, 98% purity, 70.8 μηιοΐ), [3-(methoxycarbonyl)phenyl]boronic acid (17.7 mg, 97% purity, 95.6 μηιοΐ), [l,l -Bis-(Diphenylphosphino)-ferrocen]-Dichloropalladium- Dichloromethane -complex (2.89 mg, 3.54 μηιοΐ) and potassium carbonate (19.6 mg, 142 μηιοΐ) ίη Ν,Ν- dimethylformamide (62 μΐ), water (250 μΐ) and 1,2-dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 40.3 mg (93 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 609 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.118 (0.91), 1.131 (2.53), 1.138 (2.79), 1.149 (1.28), 1.273 (1.21), 1.283 (2.80), 1.290 (2.36), 1.303 (0.93), 2.472 (3.86), 2.483 (3.28), 3.708 (3.83), 3.920 (16.00), 7.431 (1.44), 7.438 (1.44), 7.453 (1.61), 7.459 (1.63), 7.698 (1.63), 7.702 (1.40), 7.706 (1.40), 7.717 (2.61), 7.724 (1.26), 7.737 (1.43), 7.959 (1.28), 7.963 (1.40), 7.980 (1.40), 7.984 (1.61), 8.054 (4.09), 8.073 (1.46), 8.149 (1.29), 8.170 (1.21), 8.291 (2.68), 8.311 (2.35), 8.342 (2.67), 8.428 (5.98), 8.577 (2.97), 8.583 (2.99), 10.628 (2.65).
Example 63
Ethyl 3- {3-[3-( {[l -(morpholin-4-yl)cyclopropyl] carbonyl } amino) -4 -(trifluoromethoxy)phenyl] -4 -oxo - 3 ,4-dihydroquinazolin-7-yl} benzoate
Figure imgf000183_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (40.0 mg, 98% purity, 70.8 μηιοΐ), [3-(ethoxycarbonyl)-phenyl]boronic acid (19.1 mg, 97% purity, 95.6 μηιοΐ), [l,l-Bis-(Diphenylphosphino)-ferrocen]-Dichloropalladium- Dichloromethane -complex (2.89 mg, 3.54 μηιοΐ) and potassium carbonate (19.6 mg, 142 μηιοΐ) in N,N- dimethylformamide (62 μΐ), water (250 μΐ) and 1,2-dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 40.7 mg (92 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.43 min; MS (ESIpos): m/z = 623 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (1.25), 1.119 (1.53), 1.131 (4.26), 1.139 (4.81), 1.149 (2.24), 1.273 (2.05), 1.283 (4.70), 1.291 (3.89), 1.303 (1.59), 1.351 (7.48), 1.368 (16.00), 1.386 (7.62), 2.328 (0.48), 2.472 (6.57), 2.670 (0.64), 3.708 (6.44), 4.356 (2.19), 4.374 (7.11), 4.392 (7.03), 4.410 (2.13), 7.432 (2.36), 7.438 (2.37), 7.453 (2.73), 7.460 (2.78), 7.695 (2.15), 7.707 (2.45), 7.714 (4.40), 7.734 (2.86), 7.957 (2.19), 7.961 (2.30), 7.978 (2.29), 7.982 (2.64), 8.048 (6.45), 8.052 (7.03), 8.071 (2.43), 8.143 (2.10), 8.163 (2.10), 8.293 (4.39), 8.314 (3.82), 8.333 (4.46), 8.430 (9.94), 8.578 (5.07), 8.584 (5.08), 10.628 (4.47).
Example 64
Ethyl 2-fluoro-3-{3-[3-({[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}benzoate
Figure imgf000184_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (40.0 mg, 98% purity, 70.8 μηιοΐ), [3-(ethoxycarbonyl)-2- fluorophenyljboronic acid (20.9 mg, 97% purity, 95.6 μηιοΐ), [l,l -Bis-(Diphenylphosphino)-ferrocen]- Dichloropalladium-Dichloromethane-complex (2.89 mg, 3.54 μηιοΐ) and potassium carbonate (19.6 mg, 142 μηιοΐ) in N,N-dimethylformamide (62 μΐ), water (250 μΐ) and 1,2-dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 32.5 mg (97 % purity, 69 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.37 min; MS (ESIpos): m/z = 641 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.54), -0.008 (1.34), 1.120 (1.82), 1.132 (4.87), 1.140 (5.37), 1.150 (2.46), 1.233 (1.41), 1.273 (2.34), 1.283 (5.25), 1.290 (4.52), 1.303 (1.82), 1.322 (7.65), 1.339 (16.00), 1.357 (7.79), 2.473 (7.49), 2.483 (6.06), 3.708 (7.51), 4.338 (2.35), 4.356 (7.30), 4.374 (7.24), 4.392 (2.28), 7.428 (2.37), 7.435 (2.39), 7.450 (2.68), 7.457 (2.82), 7.471 (2.13), 7.490 (4.36), 7.509 (2.44), 7.708 (2.35), 7.726 (1.91), 7.730 (1.90), 7.779 (2.37), 7.799 (2.56), 7.911 (5.24), 7.938 (1.36), 7.945 (1.46), 7.949 (1.33), 7.965 (2.28), 7.981 (1.25), 7.985 (1.11), 8.283 (4.35), 8.304 (3.98), 8.426 (9.26), 8.580 (4.88), 8.586 (4.92), 10.629 (5.01).
Example 65
Methyl 4-{3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromethoxy)phenyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}pyridine-2-carboxylate
Figure imgf000185_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (85.0 mg, 62% purity, 87.8 μηιοΐ), methyl 4-bromopyridine-2-carboxylate (26.4 mg, 97 % purity, 118 μηιοΐ), [1,1 -Bis- (Diphenylphosphino)-ferrocen]-Dichloropalladium-Dichloromethane-complex (3.58 mg, 4.39 μηιοΐ) and potassium carbonate (24.3 mg, 176 μηιοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2- dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 10.5 mg (20 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.90 min; MS (ESIpos): m/z = 610 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 0.069 (0.50), 1.117 (1.31), 1.129 (3.53), 1.136 (3.70), 1.146 (1.70), 1.274 (1.76), 1.283 (3.75), 1.290 (3.10), 1.303 (1.21), 2.328 (0.44), 2.366 (0.48), 2.472 (6.14), 3.708 (5.56), 3.945 (16.00), 7.436 (1.65), 7.443 (1.54), 7.458 (1.77), 7.464 (1.84), 7.709 (1.61), 7.728 (1.35), 8.072 (1.60), 8.076 (1.61), 8.092 (1.81), 8.097 (1.84), 8.162 (1.73), 8.166 (1.77), 8.175 (1.79), 8.179 (1.79), 8.219 (3.27), 8.222 (3.11), 8.328 (2.87), 8.349 (2.41), 8.442 (3.29), 8.445 (3.27), 8.456 (5.94), 8.583 (2.88), 8.589 (2.86), 8.858 (2.58), 8.870 (2.35), 10.629 (3.31).
Example 66
Ethyl 4-fluoro-3-{3-[3-({[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}benzoate
Figure imgf000186_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (40.0 mg, 98% purity, 70.8 μηιοΐ), [5-(ethoxycarbonyl)-2- fluorophenyljboronic acid (20.9 mg, 97% purity, 95.6 μηιοΐ), [l,l -Bis-(Diphenylphosphino)-ferrocen]- Dichloropalladium-Dichloromethane-complex (2.89 mg, 3.54 μηιοΐ) and potassium carbonate (19.6 mg, 142 μηιοΐ) in N,N-dimethylformamide (62 μΐ), water (250 μΐ) and 1,2-dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 34.0 mg (75 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.44 min; MS (ESIpos): m/z = 641 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.92), 0.008 (1.63), 1.120 (1.55), 1.132 (4.42), 1.140 (4.79), 1.150 (2.24), 1.233 (0.82), 1.273 (2.13), 1.283 (4.79), 1.290 (4.06), 1.303 (1.62), 1.331 (7.47), 1.349 (16.00), 1.367 (7.60), 2.074 (0.43), 2.472 (6.74), 2.483 (5.79), 3.708 (6.65), 4.336 (2.27), 4.353 (7.17), 4.371 (7.09), 4.389 (2.18), 7.429 (2.46), 7.436 (2.40), 7.451 (2.69), 7.457 (2.74), 7.546 (1.94), 7.567 (2.42), 7.571 (2.29), 7.593 (2.05), 7.708 (2.23), 7.727 (1.89), 7.805 (2.27), 7.825 (2.45), 7.939 (4.52), 8.087 (1.10), 8.092 (1.37), 8.099 (1.28), 8.105 (1.39), 8.114 (1.42), 8.121 (1.14), 8.126 (1.25), 8.171 (2.30), 8.177 (2.07), 8.190 (2.33), 8.195 (2.07), 8.301 (4.42), 8.321 (3.92), 8.432 (9.98), 8.582 (5.17), 8.588 (5.09), 10.628 (4.53).
Example 67
Ethyl 4- {3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromethoxy)phenyl]-4-oxo- 3 ,4-dihydroquinazolin-7-yl} benzoate
Figure imgf000187_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (40.0 mg, 98% purity, 70.8 μηιοΐ), [4-(ethoxycarbonyl)phenyl]-boronic acid (19.1 mg, 97% purity, 95.6 μηιοΐ), [l ,l -Bis-(Diphenylphosphino)-ferrocen]-Dichloropalladium- Dichloromethane -complex (2.89 mg, 3.54 μηιοΐ) and potassium carbonate (19.6 mg, 142 μηιοΐ) in N,N- dimethylformamide (62 μΐ), water (250 μΐ) and 1 ,2-dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 32.8 mg (74 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.25 min; MS (ESIpos): m/z = 623 [M+H]+
Ή-ΝΜΡν (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.09), 0.008 (1.43), 1.1 17 (1.84), 1.129 (4.69), 1.137 (5.00), 1.147 (2.29), 1.232 (0.46), 1.273 (2.40), 1.283 (5.09), 1.290 (4.26), 1.303 (1.79), 1.343 (7.80), 1.361 (16.00), 1.378 (7.63), 2.328 (0.51), 2.366 (0.48), 2.472 (9.32), 2.483 (8.97), 2.670 (0.51), 3.707 (7.06), 4.338 (2.19), 4.356 (6.43), 4.373 (6.24), 4.391 (1.90), 7.430 (2.66), 7.437 (2.61), 7.452 (2.83), 7.459 (2.88), 7.702 (2.25), 7.705 (2.28), 7.724 (1.98), 7.727 (1.81), 7.979 (2.64), 7.983 (2.76), 8.000 (2.99), 8.004 (3.32), 8.014 (5.36), 8.035 (8.24), 8.098 (13.03), 8.1 19 (5.01), 8.290 (4.78), 8.31 1 (4.06), 8.430 (10.41), 8.575 (5.09), 8.582 (4.96), 10.627 (4.68).
Example 68
Methyl 5- {3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl} amino)-4-(trifluoromethoxy)phenyl]-4- 3 ,4-dihydroquinazolin-7-yl} pyridine-3 -carboxylate
Figure imgf000188_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (85.0 mg, 62% purity, 87.8 μηιοΐ), methyl 5-bromopyridine-3-carboxylate (26.4 mg, 97% purity, 118 μηιοΐ), [1,1 -Bis- (Diphenylphosphino)-ferrocen]-Dichloropalladium-Dichloromethane-complex (3.58 mg, 4.39 μηιοΐ) and potassium carbonate (24.3 mg, 176 μηιοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2- dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was submitted to preparative HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 15.0 mg (28 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.01 min; MS (ESIpos): m/z = 610 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.118 (1.01), 1.131 (2.76), 1.138 (3.08), 1.148 (1.43), 1.274 (1.39), 1.284 (3.03), 1.292 (2.60), 1.304 (1.04), 2.327 (0.72), 2.473 (4.79), 2.670 (0.66), 2.710 (0.40), 3.709 (4.44), 3.955 (16.00), 7.435 (1.47), 7.441 (1.49), 7.457 (1.70), 7.463 (1.77), 7.709 (1.43), 7.727 (1.22), 8.038 (1.42), 8.042 (1.48), 8.059 (1.61), 8.063 (1.76), 8.188 (2.97), 8.193 (2.97), 8.308 (2.84), 8.329 (2.39), 8.446 (5.95), 8.582 (2.93), 8.588 (2.94), 8.645 (1.72), 8.651 (3.05), 8.656 (1.85), 9.165 (3.02), 9.170 (3.08), 9.323 (2.95), 9.329 (2.97), 10.629 (2.79).
Example 69
N-{5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(mo^holin- 4-yl)cyclopropanecarboxamide
Figure imgf000189_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (230 mg, 69 % purity, 264 μηιοΐ), 3-bromo-5-fluoropyridine (62.8 mg, 357 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (10.8 mg, 13.2 μηιοΐ) and potassium carbonate (73.1 mg, 529 μηιοΐ) in N,N-dimethylformamide (230 μΐ), water (930 μΐ) and 1,2-dimethoxyethane (1.3 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then triturated in isopropanol, filtered and the solid was washed with diethyl ether. After drying under high vacuum, this afforded 124 mg (98 % purity, 81 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.05 min; MS (ESIpos): m/z = 570 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.134 (9.39), 1.287 (9.30), 3.709 (16.00), 7.438 (3.37), 7.452 (3.90), 7.709 (3.73), 7.724 (3.59), 8.035 (3.59), 8.051 (4.08), 8.196 (6.81), 8.302 (7.26), 8.438 (7.14), 8.584 (6.28), 8.687 (6.10), 8.989 (6.24), 10.629 (6.04).
Example 70
tert-butyl 5- {3-[3-( {[1 -(4-methylpiperazin-l -yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000189_0002
A mixture of l-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (125 mg, 52 % purity, 106 μηιοΐ), tert-butyl 5-bromopyridine-3-carboxylate (37.7 mg, 98 % purity, 143 μηιοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (8.65 mg, 10.6 μηιοΐ) and potassium carbonate (29.3 mg, 212 μηιοΐ) in N,N-dimethylformamide (93 μΐ), water (370 μΐ) and 1,2- dimethoxyethane (510 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 33.0 mg (46 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.48 min; MS (ESIpos): m/z = 665 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.124 (0.90), 1.130 (0.93), 1.138 (0.45), 1.244 (0.42), 1.252 (0.95), 1.258 (0.79), 1.611 (16.00), 2.197 (3.70), 7.419 (0.58), 7.424 (0.56), 7.437 (0.59), 7.442 (0.60), 7.698 (0.42), 7.701 (0.42), 8.021 (0.52), 8.025 (0.52), 8.038 (0.54), 8.041 (0.56), 8.165 (0.99), 8.168 (0.94), 8.304 (0.98), 8.321 (0.83), 8.442 (2.37), 8.560 (0.66), 8.565 (1.09), 8.569 (0.65), 8.634 (1.07), 8.639 (1.05), 9.111 (1.18), 9.115 (1.15), 9.277 (1.13), 9.282 (1.09), 10.662 (0.85).
Example 71
propan-2-yl 5- {3-[3-( {[l -(4-methylpiperazin-l-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000190_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (125 mg, 52 % purity, 106 μηιοΐ), propan-2-yl 5-bromopyridine-3-carboxylate (35.6 mg, 98 % purity, 143 μηιοΐ), [1,1 -bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (8.65 mg, 10.6 μηιοΐ) and potassium carbonate (29.3 mg, 212 μηιοΐ) in N,N-dimethylformamide (93 μΐ), water (370 μΐ) and 1,2- dimethoxyethane (510 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 42.0 mg (60 % yield) of the title compound. LC-MS (Method 6): Rt = 1.39 min; MS (ESIpos): m/z = 651 [M+H]+
Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 0.007 (0.79), 0.968 (0.46), 1.115 (1.07), 1.124 (2.67), 1.130 (2.71), 1.138 (1.34), 1.245 (1.28), 1.253 (2.83), 1.259 (2.32), 1.269 (1.00), 1.381 (16.00), 1.394 (15.88), 2.198 (10.04), 2.362 (0.51), 2.461 (2.81), 2.636 (0.42), 5.208 (0.44), 5.220 (1.16), 5.233 (1.55), 5.245 (1.14), 5.258 (0.46), 7.424 (1.39), 7.429 (1.37), 7.441 (1.48), 7.446 (1.51), 7.705 (1.16), 7.719 (1.02), 8.034 (1.32), 8.037 (1.34), 8.051 (1.41), 8.054 (1.46), 8.182 (2.71), 8.185 (2.60), 8.313 (2.57), 8.329 (2.25), 8.448 (5.75), 8.610 (1.67), 8.614 (2.83), 8.619 (1.69), 8.635 (2.74), 8.640 (2.69), 9.150 (2.92), 9.154 (2.83), 9.306 (2.88), 9.311 (2.81), 10.666 (2.41).
Example 72
ethyl 5- {3 -[3-( { [1 -(4-methylpiperazin- 1 -yl)cyclopropyl]carbonyl} amino)-4-(trifluoromethoxy)phenyl] - 4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000191_0001
A mixture of 1 -(4-methylpiperazin- 1 -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (250 mg, 52 % purity, 212 μιηοΐ), ethyl 5-bromopyridine-3-carboxylate (65.8 mg, 286 μιηοΐ), [l,l-bis-(diphenylphosphino)- ferrocen]-dichloropalladium-dichloromethane-complex (17.3 mg, 21.2 μιηοΐ) and potassium carbonate (58.6 mg, 424 μιηοΐ) in N,N-dimethylformamide (190 μΐ), water (740 μΐ) and 1, 2 -dimethoxy ethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 85.0 mg (62 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.29 min; MS (ESIpos): m/z = 637 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.99), 0.007 (0.70), 0.962 (0.63), 1.114 (1.62), 1.124 (4.08), 1.130 (4.27), 1.138 (2.16), 1.244 (1.95), 1.252 (4.27), 1.258 (3.57), 1.268 (1.56), 1.371 (7.08), 1.385 (14.88), 1.399 (7.07), 2.198 (16.00), 2.363 (0.54), 4.397 (2.10), 4.411 (6.55), 4.425 (6.46), 4.440 (2.01), 7.422 (2.26), 7.427 (2.23), 7.439 (2.39), 7.445 (2.49), 7.700 (1.77), 7.702 (1.82), 7.717 (1.59), 7.720 (1.48), 8.034 (2.03), 8.037 (2.11), 8.051 (2.19), 8.054 (2.34), 8.181 (4.08), 8.184 (4.03), 8.308 (3.95), 8.324 (3.38), 8.445 (9.31), 8.629 (2.76), 8.634 (7.60), 8.640 (5.17), 9.162 (4.53), 9.166 (4.52), 9.312 (4.39), 9.317 (4.43), 10.663 (3.69).
Example 73
tert-butyl 5- {3-[3-( {[l -(mo^holin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromethoxy)phenyl]-4- oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000192_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (90.0 mg, 72 % purity, 108 μηιοΐ), tert-butyl 5-bromopyridine-3-carboxylate (38.4 mg, 98 % purity, 146 μηιοΐ), [1,1 -bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (4.41 mg, 5.40 μηιοΐ) and potassium carbonate (29.8 mg, 216 μηιοΐ) in N,N-dimethylformamide (95 μΐ), water (380 μΐ) and 1,2- dimethoxyethane (520 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 56.8 mg (81 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.37 min; MS (ESIpos): m/z = 652 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.131 (0.95), 1.138 (1.05), 1.149 (0.50), 1.274 (0.47), 1.284 (1.03), 1.291 (0.88), 1.611 (16.00), 2.473 (1.45), 2.484 (1.23), 3.709 (1.42), 7.433 (0.53), 7.439 (0.53), 7.455 (0.58), 7.461 (0.61), 7.705 (0.46), 7.708 (0.48), 7.727 (0.41), 8.023 (0.49), 8.027 (0.51), 8.044 (0.53), 8.048 (0.57), 8.170 (1.03), 8.174 (0.98), 8.306 (1.02), 8.327 (0.87), 8.445 (2.24), 8.563 (0.60), 8.568 (1.08), 8.573 (0.64), 8.583 (1.11), 8.589 (1.10), 9.113 (1.12), 9.117 (1.10), 9.281 (1.08), 9.286 (1.05), 10.629 (0.98).
Example 74
ethyl 5-{3-[3-({[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromethoxy)phenyl]-4- 3 ,4-dihydroquinazolin-7-yl} pyridine-3 -carboxylate
Figure imgf000193_0001
A mixture of l -(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide (90.0 mg, 72 % purity, 108 μηιοΐ), ethyl 5-bromopyridine-3-carboxylate (34.2 mg, 98 % purity, 146 μηιοΐ), [1,1 -bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (4.41 mg, 5.40 μηιοΐ) and potassium carbonate (29.8 mg, 216 μηιοΐ) in N,N-dimethylformamide (95 μΐ), water (380 μΐ) and 1,2- dimethoxyethane (520 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 49.0 mg (100 % purity, 73 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.14 min; MS (ESIpos): m/z = 624 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.47), -0.008 (1.96), 0.008 (1.91), 1.118 (1.69), 1.131 (4.74), 1.138 (5.34), 1.148 (2.52), 1.233 (1.13), 1.274 (2.34), 1.284 (5.13), 1.291 (4.34), 1.304 (1.75), 1.357 (0.67), 1.367 (7.58), 1.375 (1.63), 1.385 (16.00), 1.403 (7.72), 2.473 (7.32), 2.484 (6.16), 2.670 (0.44), 2.710 (0.42), 3.709 (7.24), 4.392 (2.39), 4.410 (7.47), 4.428 (7.39), 4.446 (2.32), 7.435 (2.42), 7.441 (2.44), 7.457 (2.77), 7.463 (2.84), 7.705 (2.15), 7.709 (2.23), 7.727 (1.94), 7.731 (1.77), 8.035 (2.38), 8.040 (2.48), 8.056 (2.66), 8.060 (2.87), 8.186 (4.87), 8.190 (4.72), 8.310 (4.59), 8.331 (3.90), 8.446 (9.67), 8.583 (4.57), 8.589 (4.57), 8.632 (2.92), 8.638 (5.12), 8.643 (3.05), 9.164 (4.12), 9.169 (4.11), 9.316 (4.99), 9.321 (4.91), 10.629 (4.78).
Example 75
N-{5-[7-(2-aminopyrimidin-5-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2- (morpholin-4-yl)propanamide (racemate)
Figure imgf000194_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (100 mg, 70 % purity, 119 μηιοΐ), 5-bromopyrimidin-2-amine (28.5 mg, 98 % purity, 161 μιηοΐ), [l,l -bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (4.86 mg, 5.95 μmol) and potassium carbonate (32.9 mg, 238 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (420 μΐ) and 1,2-dimethoxyethane (580 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 60°C for lh. The reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 45.6 mg (100 % purity, 69 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.37 min; MS (ESIpos): m/z = 556 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.61), 0.008 (2.84), 1.196 (8.71), 1.214 (8.84), 2.328 (0.47), 2.565 (4.45), 2.576 (2.49), 2.594 (0.97), 2.605 (0.55), 2.670 (0.49), 2.710 (0.41), 3.381 (0.76), 3.398 (2.47), 3.416 (2.39), 3.433 (0.65), 3.646 (3.78), 3.657 (6.61), 3.667 (3.79), 7.006 (7.49), 7.434 (1.87), 7.440 (1.85), 7.456 (2.15), 7.462 (2.22), 7.663 (1.75), 7.667 (1.85), 7.685 (1.50), 7.899 (1.82), 7.904 (1.97), 7.920 (2.05), 7.925 (2.28), 8.016 (3.92), 8.020 (3.82), 8.202 (3.68), 8.222 (3.13), 8.391 (7.76), 8.406 (3.49), 8.413 (3.46), 8.796 (16.00), 10.091 (3.87).
Example 76
N-{5-[7-(4-Methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(morpholin- 4-yl)propanamide (racemate)
Figure imgf000195_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (200 mg, 69% purity, 235 μιηοΐ), 3-bromo-4-methylpyridine (36 μΐ, 320 μmol), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (9.58 mg, 11.7 μιηοΐ) and potassium carbonate (64.8 mg, 469 μιηοΐ) in N,N-dimethylformamide (210 μΐ), water (820 μΐ) and 1,2-dimethoxyethane (1.1 ml) was degassed by passing argon through it for 5 min and then heated at 80°C for 1 h. The reaction mixture was then filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 106 mg (80 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.39 min; MS (ESIneg): m/z = 552 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.87), 0.008 (0.82), 1.202 (7.11), 1.219 (7.20), 2.323 (16.00), 2.524 (1.28), 2.569 (3.49), 2.581 (1.95), 2.600 (0.77), 3.387 (0.57), 3.405 (1.64), 3.422 ( 1.60), 3.439 (0.49), 3.650 (3.43), 3.661 (5.79), 3.671 (3.30), 7.408 (2.37), 7.421 (2.44), 7.446 (1.69), 7.453 (1.67), 7.468 (1.99), 7.474 (2.02), 7.641 (1.91), 7.645 (2.01), 7.661 (1.98), 7.665 (2.19), 7.678 (1.67), 7.681 (1.71), 7.700 (1.39), 7.703 (1.32), 7.773 (3.48), 7.776 (3.38), 8.274 (3.23), 8.295 (3.08), 8.429 (9.59), 8.436 (3.09), 8.486 (5.26), 8.508 (3.10), 8.520 (3.01), 10.104 (2.87).
Example 77
2-(4-Methylpiperazin- 1 -yl)-N-[5-(4-oxo-7-phenylquinazolin
(trifluoromethoxy)phenyl]propanamide (racemate)
Figure imgf000195_0002
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (Racemate) (340 mg, 53% purity, 300 μιηοΐ), bromobenzene (63.6 mg, 405 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (24.5 mg, 30.0 μιηοΐ) and potassium carbonate (82.9 mg, 600 μιηοΐ) in N,N-dimethylformamide (270 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.5 ml) was degassed by passing argon through it for 5 min and then heated at 80°C for 2 h. The reaction mixture was then filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 89.0 mg (54 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.77 min; MS (ESIpos): m/z = 552 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.60), 0.008 (2.45), 1.183 (8.37), 1.200 (8.46), 2.182 (16.00), 2.328 (0.78), 2.367 (1.10), 2.404 (1.14), 2.524 (2.04), 2.565 (3.32), 2.670 (0.54), 2.710 (0.47), 3.402 (0.69), 3.420 (2.40), 3.437 (2.34), 3.454 (0.65), 7.424 (1.98), 7.430 (1.95), 7.446 (2.24), 7.452 (2.34), 7.464 (0.78), 7.483 (2.40), 7.501 (1.93), 7.537 (3.16), 7.557 (4.67), 7.575 (1.95), 7.671 (1.79), 7.675 (1.84), 7.693 (1.55), 7.697 (1.43), 7.854 (4.53), 7.872 (4.15), 7.876 (3.05), 7.929 (1.95), 7.934 (2.09), 7.950 (2.13), 7.954 (2.40), 8.015 (4.04), 8.019 (3.70), 8.264 (3.77), 8.285 (3.30), 8.417 (7.99), 8.504 (3.54), 8.511 (3.50), 10.155 (3.57).
Example 78
2-(4-Methylpiperazin-l-yl)-N-{5-[7-(4-methylpyridin-3-yl)-4-oxoquinazolin
(trifluoromethoxy)phenyl}propanamide (racemate)
Figure imgf000196_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (340 mg, 53%> purity, 300 μιηοΐ), 3-bromo-4-methylpyridine (69.7 mg, 405 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (24.5 mg, 30.0 μιηοΐ) and potassium carbonate (82.9 mg, 600 μιηοΐ) in N,N-dimethylformamide (270 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.5 ml) was degassed by passing argon through it for 5 min and then heated at 80°C for 2 h. The reaction mixture was then filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 87: 13. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 100 mg (96 % purity, 56 % yield) of the title compound.
LC-MS (Method 6): Rt = 0.86 min; MS (ESIpos): m/z =567 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.96), 0.008 (1.98), 1.185 (7.30), 1.203 (7.39), 2.183 (14.01), 2.323 (16.00), 2.366 (1.04), 2.405 (1.04), 2.523 (1.91), 2.665 (0.45), 2.670 (0.57), 2.674 (0.45), 2.710 (0.46), 3.404 (0.65), 3.422 (2.12), 3.439 (2.07), 3.457 (0.59), 7.408 (2.41), 7.420 (2.57), 7.426 (2.15), 7.432 (1.80), 7.448 (1.98), 7.454 (2.04), 7.641 (1.88), 7.645 (1.99), 7.661 (2.01), 7.665 (2.25), 7.677 (1.63), 7.680 (1.71), 7.699 (1.37), 7.702 (1.31), 7.772 (3.44), 7.776 (3.41), 8.275 (3.25), 8.295 (3.04), 8.431 (7.12), 8.485 (5.50), 8.508 (3.59), 8.513 (3.49), 8.520 (6.25), 10.159 (3.20). Example 79
N-{5-[7-(2-Fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(4- methylpiperazin-1 -yl)propanamide (racemate)
Figure imgf000197_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (racemate) (400 mg, 60% purity, 399 μιηοΐ), 1 -bromo-2-fluorobenzene (94.3 mg, 539 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (32.6 mg, 39.9 μιηοΐ) and potassium carbonate (110 mg, 798 μιηοΐ) in N,N-dimethylformamide (350 μΐ), water (1.4 ml) and 1,2-dimethoxyethane (1.9 ml) was degassed by passing argon through it for 5 min and then heated at 80°C for 1.5 h. The reaction mixture was then filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2%> ammonia) to deliver 135 mg (59 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.41 min; MS (ESIneg): m/z = 568 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.25), 0.008 (1.55), 1.183 (8.58), 1.201 (8.55), 2.182 (16.00), 2.328 (0.85), 2.403 (1.27), 2.670 (0.61), 3.403 (0.75), 3.420 (2.47), 3.438 (2.37), 3.455 (0.65), 7.370 (1.24), 7.372 (1.41), 7.382 (1.45), 7.391 (2.79), 7.403 (2.06), 7.408 (2.97), 7.423 (2.50), 7.429 (3.45), 7.445 (2.42), 7.451 (2.40), 7.508 (0.76), 7.512 (0.84), 7.521 (0.92), 7.525 (1.33), 7.546 (1.06), 7.559 (0.53), 7.674 (2.06), 7.678 (2.10), 7.684 (1.69), 7.688 (1.52), 7.696 (2.07), 7.703 (2.61), 7.708 (1.95), 7.724 (1.06), 7.728 (0.91), 7.788 (2.11), 7.808 (2.23), 7.907 (3.77), 8.279 (3.76), 8.299 (3.40), 8.424 (8.12), 8.509 (3.79), 8.516 (3.62), 10.156 (3.64).
Example 80
ethyl 5-{3-[4-(difluoromethoxy)-3- {[l -(morpholin-4-yl)cyclopropane-l -carbonyl]amino}phenyl]-4-oxo- 3 ,4-dihydroquinazolin-7-yl} pyridine-3 -carboxylate
Figure imgf000198_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 93.4 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine-3 -carboxylate (51.8 mg, 187 μιηοΐ), [l,l '-bis-(diphenylphosphino)-ferrocen]- dichloropalladium (10.8 mg, 9.34 μιηοΐ) and sodium carbonate (39.6 mg, 374 μιηοΐ) in 1,4-dioxane (5.9 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 10:90 to afford 29.0 mg (99 % purity, 51 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.97 min; MS (ESIpos): m/z = 606 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.24), 0.006 (0.80), 1.107 (1.60), 1.117 (4.33), 1.123 (4.33), 1.131 (1.96), 1.252 (2.01), 1.260 (4.57), 1.266 (3.81), 1.276 (1.56), 1.371 (7.58), 1.385 (16.00), 1.399 (7.54), 2.462 (5.13), 3.341 (0.48), 3.497 (0.48), 3.648 (1.44), 3.732 (5.85), 4.094 (0.56), 4.133 (0.88), 4.397 (2.33), 4.411 (7.18), 4.425 (7.02), 4.439 (2.17), 7.355 (3.09), 7.360 (2.53), 7.372 (2.65), 7.377 (2.69), 7.504 (5.13), 7.507 (3.97), 7.524 (2.73), 7.651 (1.84), 8.030 (2.37), 8.034 (2.37), 8.047 (2.49), 8.050 (2.57), 8.178 (4.61), 8.181 (4.33), 8.306 (4.45), 8.323 (3.81), 8.410 (10.27), 8.551 (4.85), 8.556 (4.69), 8.630 (2.97), 8.634 (4.97), 8.638 (2.89), 9.162 (5.13), 9.166 (4.97), 9.312 (5.01), 9.316 (4.85), 10.692 (4.09).
Example 81
N-{2-(difluoromethoxy)-5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]phenyl}-l -(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000199_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (65.0 mg, 121 μιηοΐ), (5-fluoropyridin-3-yl)boronic acid (34.2 mg, 243 μιηοΐ), [l, -bis-(diphenylphosphino)-ferrocen]-dichloropalladium (9.92 mg, 12.1 μmol) and sodium carbonate (51.5 mg, 486 μιηοΐ) in 1,4-dioxane (7.7 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. Due to partial conversion, (5-fluoropyridin- 3-yl)boronic acid (17.1 mg, 121 μιηοΐ), [l,l '-bis-(diphenylphosphino)-ferrocen]-dichloropalladium (7.02 mg, 6.07 μιηοΐ) and sodium carbonate (25.7 mg, 243 μιηοΐ) were added and the reaction mixture was allowed to stir at 105 °C overnight. This action was repeated twice more until complete consumption of the starting material. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100. The product fractions were collected and purified twice more by preparative RP-HPLC 125x30mm, with acetonitrile/water (first with 0.1% formic acid and then in neutral conditions), to afford 7.00 mg (10 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 552 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.106 (2.96), 1.114 (8.69), 1.119 (8.66), 1.126 (3.84), 1.232 (0.88), 1.256 (3.71), 1.263 (8.96), 1.268 (7.88), 1.276 (3.10), 2.387 (0.71), 2.615 (0.57), 3.731 (10.27), 7.356 (3.81), 7.360 (3.84), 7.370 (4.41), 7.375 (4.51), 7.390 (3.27), 7.512 (9.06), 7.525 (5.22), 7.635 (3.00), 8.035 (4.08), 8.038 (4.18), 8.049 (4.38), 8.052 (4.61), 8.197 (8.35), 8.200 (8.29), 8.283 (7.78), 8.298 (6.74), 8.311 (2.32), 8.315 (3.40), 8.318 (2.46), 8.327 (2.29), 8.331 (3.33), 8.335 (2.43), 8.411 (16.00), 8.550 (8.08), 8.555 (7.92), 8.688 (7.48), 8.693 (7.28), 8.994 (7.81), 10.704 (8.15).
Example 82
N- {2-(difluoromethoxy)-5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]phenyl} -1 -(4-methylpiperazin-l - yl)cyclopropane-l -carboxamide
Figure imgf000200_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (65.0 mg, 119 μιηοΐ), pyridin-3-ylboronic acid (29.1 mg, 237 μιηοΐ), [l, -bis-(diphenylphosphino)-ferrocen]-dichloropalladium (9.68 mg, 11.9 μιηοΐ) and sodium carbonate (50.3 mg, 474 μιηοΐ) in 1,4-dioxane (7.5 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. Due to partial conversion, pyridin-3- ylboronic acid (16.7 mg, 136 μιηοΐ), [l,l '-bis-(diphenylphosphino)-ferrocen]-dichloropalladium (6.85 mg, 5.93 μιηοΐ) and sodium carbonate (25.1 mg, 237 μιηοΐ) were added and the reaction mixture was allowed to stir at 105 °C overnight. This action was repeated once more until complete consumption of the starting material. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified twice by chromatography over silica gel eluting with a gradient DCM/methanol from 95:5 to 80:20. The product fractions were collected and purified by preparative RP-HPLC 125x30mm, with acetonitrile/water (0.2% ammonia) to afford 22.0 mg (34 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.02 min; MS (ESIneg): m/z = 545 [M-H]"
Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.105 (3.04), 1.113 (8.53), 1.117 (8.70), 1.124 (4.11), 1.151 (0.45), 1.191 (0.47), 1.218 (4.18), 1.225 (9.73), 1.230 (9.69), 1.238 (3.77), 2.270 (5.69), 2.388 (1.02), 2.616 (1.37), 7.351 (3.93), 7.355 (3.78), 7.365 (4.55), 7.369 (4.52), 7.380 (3.07), 7.501 (9.96), 7.515 (5.60), 7.562 (3.58), 7.570 (3.81), 7.575 (3.75), 7.583 (3.72), 7.625 (2.76), 7.986 (4.53), 7.988 (4.44), 7.999 (4.76), 8.002 (4.82), 8.114 (9.32), 8.116 (8.88), 8.281 (10.83), 8.295 (10.08), 8.398 (16.00), 8.550 (5.12), 8.671 (5.21), 8.672 (5.10), 8.678 (5.19), 9.077 (7.42), 9.081 (7.38), 10.665 (2.15).
Example 83
ethyl 5-{3-[4-(difluoromethoxy)-3- {[l -(4-methylpiperazin-l-yl)cyclopropane-l- carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyridine-3 -carboxylate
Figure imgf000201_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (65.0 mg, 119 μmol), ethyl 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (65.7 mg, 237 μιηοΐ), [l,l '-bis-(diphenylphosphino)- ferrocenj-dichloropalladium (9.68 mg, 11.9 μιηοΐ) and sodium carbonate (50.3 mg, 474 μιηοΐ) in 1,4- dioxane (7.5 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. Due to partial conversion, ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-3-carboxylate (16.8 mg, 60.5 μιηοΐ), [l,l '-bis-(diphenylphosphino)-ferrocen]- dichloropalladium (6.85 mg, 5.93 μιηοΐ) and sodium carbonate (25.1 mg, 237 μιηοΐ) were added and the reaction mixture was allowed to stir at 105 °C overnight. This action was repeated once more until complete consumption of the starting material. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified twice by chromatography over silica gel eluting with a gradient DCM/methanol from 95:5 to 80:20. During The product fractions were collected and purified by preparative RP-HPLC 250x30mm, with acetonitrile/water (neutral conditions) to afford 22.5 mg (31 % yield) of the title compound and 4.00 mg (90 % purity) of a side product corresponding to the methyl ester described in Example 6.
LC-MS (Method 6): Rt = 1.30 min; MS (ESIneg): m/z = 617 [M-H]"
Ή-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (1.10), 1.097 (1.33), 1.105 (4.03), 1.110 (4.01), 1.117 (1.84), 1.217 (1.69), 1.224 (4.23), 1.229 (3.63), 1.237 (1.48), 1.372 (6.45), 1.384 (13.42), 1.396 (6.49), 2.206 (16.00), 2.388 (0.67), 2.452 (1.96), 4.399 (1.99), 4.411 (6.14), 4.423 (6.02), 4.434 (1.91), 7.349 (1.92), 7.353 (1.88), 7.363 (2.19), 7.367 (2.24), 7.389 (1.65), 7.502 (3.31), 7.511 (3.68), 7.516 (2.78), 7.634 (1.56), 8.034 (2.02), 8.037 (2.01), 8.048 (2.14), 8.051 (2.21), 8.182 (4.23), 8.185 (4.00), 8.303 (3.81), 8.317 (3.33), 8.415 (8.34), 8.578 (4.13), 8.582 (4.07), 8.632 (2.41), 8.635 (4.20), 8.639 (2.39), 9.163 (4.26), 9.166 (4.20), 9.316 (4.24), 9.320 (4.13), 10.719 (3.81).
Example 84
methyl 5- {3-[4-(difluoromethoxy)-3-{[l-(4-methylpiperazin-l -yl)cyclopropane-l- carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyridine-3 -carboxylate
Figure imgf000202_0001
LC-MS (Method 6): Rt = 1.20 min; MS (ESIneg): m/z = 603 [M-H]"
Ή- MR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.55), 1.097 (1.06), 1.105 (2.73), 1.110 (2.72), 1.117 (1.26), 1.219 (1.33), 1.225 (2.91), 1.230 (2.51), 1.239 (1.01), 2.206 (10.62), 2.388 (0.55), 2.452 (1.38), 3.954 (16.00), 7.350 (1.32), 7.354 (1.28), 7.364 (1.50), 7.368 (1.54), 7.390 (1.09), 7.503 (2.28), 7.512 (2.46), 7.517 (1.83), 7.635 (1.03), 8.040 (1.37), 8.043 (1.38), 8.054 (1.47), 8.057 (1.51), 8.188 (2.83), 8.191 (2.77), 8.305 (2.68), 8.318 (2.31), 8.417 (5.66), 8.577 (2.74), 8.581 (2.70), 8.647 (1.66), 8.651 (2.90), 8.654 (1.67), 9.165 (2.86), 9.168 (2.84), 9.326 (2.90), 9.330 (2.84), 10.722 (2.48).
Example 85
tert-butyl [1 -( {5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2
(trifluoromethoxy)phenyl}carbamoyl)cyclopropyl]carbamate
Figure imgf000202_0002
A mixture of tert-butyl (l-{[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-
(trifluoromethoxy)phenyl]carbamoyl}cyclopropyl)carbamate (50.0 mg, 85.7 μιηοΐ), 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (47.5 mg, 50 % purity, 116 μιηοΐ), [1,1 -Bis- (Diphenylphosphino)-ferrocene]-dichloropalladium-dichloromethanecomplex (7.00 mg, 8.57 μιηοΐ) and potassium carbonate (23.7 mg, 171 μιηοΐ) in DMF (75 μΐ), water (300 μΐ) and 1 ,2-dimethoxyethane (410 μΐ) was degassed by passing an argon stream through it for 5 min. The reaction mixture was then stirred at 80°C for 90 min. The mixture was passed through a silica gel column, eluting with a gradient of dichloromethane/MeOH from 100:0 to 85: 15. The material recovered was then purified by preparative RP-HPLC 125x30mm with acetonitrile/water to provide the title product. 30.9 mg (62 % yield).
LC-MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 582 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.064 (1.11), 1.073 (2.75), 1.079 (2.63), 1.088 (1.15), 1.381 (3.04), 1.387 (2.99), 1.397 (2.09), 1.419 (16.00), 2.073 (0.62), 7.452 (0.90), 7.469 (1.03), 7.560 (1.17), 7.569 (1.27), 7.575 (1.23), 7.585 (1.17), 7.667 (1.23), 7.684 (1.01), 7.875 (0.50), 7.985 (1.45), 7.988 (1.43), 8.002 (1.55), 8.005 (1.55), 8.112 (2.97), 8.115 (2.75), 8.279 (1.49), 8.283 (1.25), 8.290 (3.34), 8.306 (2.33), 8.402 (0.56), 8.435 (4.96), 8.669 (1.71), 8.672 (1.65), 8.678 (1.67), 8.681 (1.51), 9.074 (2.41), 9.078 (2.31), 9.262 (0.72). Example 86
ethyl 5-{8-fluoro-3-[3-{[l -(morpholin-4-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000203_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (70.0 mg, 123 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (67.9 mg, 245 μιηοΐ), [l,l '-bis-(diphenylphosphino)- ferrocenj-dichloropalladium (10.0 mg, 12.3 μιηοΐ) and sodium carbonate (51.9 mg, 490 μιηοΐ) in 1,4- dioxane (7.7 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. Due to partial of the starting material additional ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (34.0 mg, 123 μιηοΐ), [l,l '-bis-(diphenylphosphino)- ferrocenj-dichloropalladium (5.00 mg, 6.13 μιηοΐ) and sodium carbonate (26.0 mg, 245 μιηοΐ) were added and the reaction mixture was allowed to stir for 15 h at 105 °C. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient dichloromethane/ethanol from 99: 1 to 85:15. The product fractions were collected and purified one more time by preparative RP-HPLC 250x30mm with acetonitrile/water (neutral conditions) to afford 33.0 mg (42 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.19 min; MS (ESIpos): m/z = 642 [M+H]+ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.07), 0.008 (2.60), 1.120 (1.64), 1.133 (4.16), 1.140 (4.36), 1.150 (2.03), 1.234 (1.95), 1.287 (4.38), 1.294 (3.97), 1.307 (1.51), 1.356 (7.48), 1.374 (16.00), 1.391 (7.56), 2.073 (1.56), 2.328 (1.53), 2.366 (1.21), 2.474 (7.01), 2.670 (1.42), 2.711 (0.99), 3.710 (6.00), 4.388 (2.30), 4.406 (7.26), 4.423 (7.12), 4.441 (2.08), 7.437 (2.38), 7.443 (2.47), 7.458 (2.71), 7.465 (2.79), 7.722 (2.11), 7.740 (1.89), 7.856 (1.56), 7.876 (2.27), 7.894 (1.95), 8.110 (3.51), 8.131 (2.93), 8.498 (8.77), 8.552 (3.37), 8.601 (4.90), 8.608 (4.88), 9.143 (3.62), 9.192 (5.32), 9.197 (5.40), 10.636 (4.44).
Example 87
N-{5-[7-(5-chloropyridin-3-yl)-8-fluoro-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l - (morpholin-4-yl)cyclopropane- 1 -carboxamide
Figure imgf000204_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l -carboxamide (70.0 mg, 123 μιηοΐ), (5-chloropyridin-3-yl)boronic acid (28.9 mg, 184 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium (5.00 mg, 6.13 μιηοΐ) and potassium carbonate (50.8 mg, 368 μιηοΐ) in N,N-dimethylformamide (110 μΐ), water (440 μ) and 1 ,2-dimethoxyethane (610 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 98:2 to 90: 10 (+ 0.2% ammonia). The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2%> ammonia) to deliver two fractions, 19.0 mg (100 % purity, 26 % yield) and 33.0 mg (95 % purity, 42 % yield), of the title compound (68 % total yield).
LC-MS (Method 6): Rt = 2.22 min; MS (ESIpos): m/z = 604 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 0.146 (0.51), 1.118 (3.02), 1.131 (8.53), 1.138 (9.41), 1.148 (4.35), 1.234 (1.60), 1.275 (4.28), 1.286 (9.38), 1.293 (7.92), 1.305 (3.13), 1.478 (1.32), 1.636 (0.48), 2.327 (1.43), 2.366 (1.36), 2.473 (13.55), 2.670 (1.46), 2.710 (1.39), 3.708 (13.04), 7.430 (4.48), 7.436 (4.52), 7.452 (5.10), 7.458 (5.13), 7.720 (4.11), 7.739 (3.60), 7.824 (3.30), 7.845 (4.48), 7.862 (3.84), 8.088 (6.83), 8.109 (5.74), 8.321 (7.30), 8.492 (16.00), 8.597 (9.14), 8.604 (9.27), 8.770 (8.63), 8.775 (8.19), 8.862 (8.46), 10.634 (8.80).
Example 88
N-{5-[8-fluoro-7-(5-fluoropyridin-3-yl)-4-ox
(morpholin-4-yl)cyclopropane- 1 -carboxamide
Figure imgf000205_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l -carboxamide (70.0 mg, 123 μιηοΐ), (5-fluoropyridin-3-yl)boronic acid (27.3 mg, 95 % purity, 184 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]-dichloropalladium (5.00 mg, 6.13 μιηοΐ) and potassium carbonate (50.8 mg, 368 μιηοΐ) in N,N-dimethylformamide (110 μΐ), water (440 μ) and 1 ,2-dimethoxyethane (610 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. After cooling to rt, the solvent was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 90: 10 (+ 0.2% ammonia). The product fractions were collected and purified once more by preparative RP-HPLC 125x30mm, with acetonitrile/water (0.2% ammonia), to afford 28.5 mg (98 % purity, 38 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.09 min; MS (ESIpos): m/z = 588 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.118 (3.09), 1.131 (8.73), 1.138 (9.49), 1.148 (4.37), 1.233 (0.74), 1.276 (4.21), 1.286 (9.44), 1.293 (7.92), 1.306 (3.33), 1.479 (0.48), 2.327 (1.00), 2.366 (0.93), 2.472 (13.55), 2.670 (1.21), 2.710 (0.97), 3.708 (13.15), 7.430 (4.68), 7.436 (4.54), 7.452 (5.16), 7.458 (5.14), 7.717 (4.14), 7.720 (4.09), 7.739 (3.68), 7.823 (3.42), 7.843 (4.35), 7.860 (3.66), 8.092 (6.61), 8.113 (5.54), 8.142 (3.19), 8.166 (3.23), 8.493 (16.00), 8.598 (9.44), 8.605 (9.30), 8.728 (8.34), 8.735 (8.06), 8.789 (6.85), 10.634 (8.75).
Example 89
N-{5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(methoxymethyl)phenyl} -l -(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000206_0001
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(morpholin-4-yl)cyclopropane-l-carboxamide (92.6 mg, 69 % purity, 114 μιηοΐ), 3-bromo-5-fluoropyridine (27.1 mg, 154 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.65 mg, 5.70 μιηοΐ) and potassium carbonate (31.5 mg, 228 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1,2-dimethoxyethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h and then let to stir at rt overnight. The reaction mixture was then partitioned between water and dichloromethane. After extractive work-up the combined organic layers were dried over Na2S04, filtered and evaporated. The residue was purified by column chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water to deliver 20.5 mg (98 % purity, 33 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.78 min; MS (ESIpos): m/z = 530 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.100 (4.57), 1.221 (4.63), 2.074 (1.36), 3.353 (16.00), 3.735 (8.48), 4.668 (7.50), 7.275 (1.88), 7.295 (2.15), 7.541 (2.69), 7.562 (2.48), 8.027 (1.96), 8.048 (2.28), 8.192 (4.03), 8.284 (3.09), 8.303 (3.61), 8.322 (2.06), 8.373 (3.87), 8.404 (4.89), 8.682 (3.32), 8.988 (3.59), 10.737 (3.31).
Example 90
N-{5-[7-(5-chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(methoxymethyl)phenyl} -l -(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000206_0002
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(morpholin-4-yl)cyclopropane-l-carboxamide (92.6 mg, 69 % purity, 114 μιηοΐ), 3-bromo-5-chloropyridine (29.6 mg, 154 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.65 mg, 5.70 μιηοΐ) and potassium carbonate (31.5 mg, 228 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1 ,2-dimethoxyethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h and then let to stir at rt overnight. The reaction mixture was then partitioned between water and dichloromethane. After extractive work-up the combined organic layers were dried over Na2S04, filtered and evaporated. The residue was purified by column chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water to deliver 29.9 mg (100 % purity, 48 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.93 min; MS (ESIpos): m/z = 546 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.083 (0.97), 1.095 (2.61), 1.102 (3.05), 1.112 (1.52), 1.211 (1.43), 1.220 (3.05), 1.227 (2.57), 1.240 (1.07), 3.342 (1.66), 3.354 (16.00), 3.725 (3.64), 3.736 (5.09), 3.746 (3.50), 4.667 (6.03), 7.271 (1.32), 7.277 (1.27), 7.291 (1.46), 7.296 (1.43), 7.541 (2.21), 7.561 (1.92), 8.021 (1.28), 8.025 (1.31), 8.042 (1.46), 8.046 (1.50), 8.187 (2.82), 8.191 (2.71), 8.279 (2.44), 8.300 (2.05), 8.369 (2.63), 8.374 (2.71), 8.403 (4.99), 8.470 (1.56), 8.475 (2.66), 8.480 (1.61), 8.723 (2.50), 8.729 (2.39), 9.048 (2.70), 9.053 (2.62), 10.736 (2.44).
Example 91
N- {2-(methoxymethyl)-5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]phenyl} -1 -(4-methylpiperazin-l - yl)cyclopropane-l -carboxamide
Figure imgf000207_0001
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(4-methylpiperazin-l -yl)cyclopropane-l -carboxamide (65.4 mg, 114 μιηοΐ), 3-bromopyridine (24.3 mg, 154 μιηοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.65 mg, 5.70 μιηοΐ) and potassium carbonate (31.5 mg, 228 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1,2-dimethoxyethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h and then stored at -18°C overnight. The reaction mixture was then filtered thorugh a silica gel column eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water to deliver 17.3 mg (29 % yield) of the title compound.
LC-MS (Method 6): Rt = 0.94 min; MS (ESIneg): m/z = 523 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.072 (0.93), 1.085 (2.35), 1.092 (2.83), 1.102 (1.44), 1.177 (1.44), 1.187 (2.90), 1.194 (2.26), 1.206 (0.99), 1.236 (0.70), 1.329 (0.68), 1.353 (0.46), 2.228 (3.91), 2.366 (0.44), 2.455 (2.88), 3.383 (16.00), 4.635 (6.04), 7.267 (1.25), 7.272 (1.25), 7.287 (1.40), 7.292 (1.42), 7.537 (2.26), 7.556 (2.73), 7.567 (1.27), 7.574 (1.20), 7.586 (1.16), 7.980 (1.31), 7.985 (1.39), 8.001 (1.48), 8.005 (1.59), 8.112 (2.66), 8.116 (2.58), 8.278 (1.37), 8.285 (2.87), 8.299 (1.35), 8.306 (2.41), 8.354 (2.18), 8.359 (2.20), 8.395 (4.88), 8.666 (1.40), 8.669 (1.42), 8.678 (1.44), 8.681 (1.40), 9.075 (2.09), 9.080 (2.13), 10.628 (1.94).
Example 92
ethyl 5 - {3 -[4-(methoxymethyl)-3 - { [ 1 -(4-methylpiperazin- 1 -yl)cyclopropane- 1 -carbonyl] amino } phenyl] - 4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000208_0001
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(4-methylpiperazin-l-yl)cyclopropane-l -carboxamide (65.4 mg, 114 μιηοΐ), ethyl 5-bromopyridine-3-carboxylate (35.4 mg, 154 μιηοΐ), [l,l -bis-(diphenylphosphino)- ferrocen]-dichloropalladium-dichloromethane-complex (4.65 mg, 5.70 μιηοΐ) and potassium carbonate (31.5 mg, 228 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1 ,2-dimethoxyethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h and then stored at -18°C overnight. The reaction mixture was then filtered thorugh a silica gel column eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water to deliver 18.3 mg (27 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.26 min; MS (ESIneg): m/z = 595 [M-H] Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.46), 1.070 (0.80), 1.083 (2.02), 1.090 (2.45), 1.100 (1.20), 1.177 (1.17), 1.186 (2.46), 1.193 (1.86), 1.206 (0.82), 1.234 (0.42), 1.367 (3.72), 1.385 (7.91), 1.403 (3.79), 2.209 (9.69), 3.386 (16.00), 4.392 (1.15), 4.409 (3.64), 4.427 (3.60), 4.445 (1.13), 4.634 (5.31), 7.271 (1.17), 7.276 (1.15), 7.291 (1.27), 7.296 (1.30), 7.538 (2.00), 7.558 (1.76), 8.030 (1.15), 8.034 (1.16), 8.050 (1.29), 8.055 (1.36), 8.180 (2.35), 8.184 (2.23), 8.308 (2.19), 8.329 (1.93), 8.365 (2.17), 8.370 (2.15), 8.413 (4.72), 8.631 (1.40), 8.637 (2.46), 8.642 (1.44), 9.162 (2.06), 9.167 (2.01), 9.314 (2.35), 9.320 (2.32), 10.637 (2.05).
Example 93
N-{5-[7-(5-chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(methoxymethyl)phenyl} -l -(4- methylpiperazin- 1 -yl)cyclopropane- 1 -carboxamide
Figure imgf000209_0001
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(4-methylpiperazin-l-yl)cyclopropane-l -carboxamide (65.4 mg, 114 μηιοΐ), 3-bromo-5-chloropyridine (29.6 mg, 154 μηιοΐ), [l,l -bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.65 mg, 5.70 μηιοΐ) and potassium carbonate (31.5 mg, 228 μηιοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1,2-dimethoxyethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1.5 h and then stored at -18°C overnight. The reaction mixture was then filtered thorugh a silica gel column eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water to deliver 20.0 mg (100 % purity, 31 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.27 min; MS (ESIpos): m/z = 559 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.069 (0.92), 1.082 (2.53), 1.089 (3.06), 1.098 (1.49), 1.176 (1.39), 1.186 (2.96), 1.205 (0.97), 2.210 (10.53), 3.384 (16.00), 4.632 (6.28), 7.265 (1.26), 7.270 (1.29), 7.285 (1.39), 7.289 (1.49), 7.535 (2.21), 7.555 (1.94), 8.024 (1.45), 8.044 (1.62), 8.190 (2.98), 8.277 (2.12), 8.298 (1.77), 8.361 (2.99), 8.366 (2.98), 8.402 (4.71), 8.474 (2.51), 8.723 (2.38), 8.728 (2.49), 9.052 (2.80), 10.634 (2.52). Example 94
N-{5-[6-fluoro-4-oxo-7-(pyridin-3-yl)quinazoH^
4-yl)cyclopropane-l -carboxamide
Figure imgf000210_0001
A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l -carboxamide (50.0 mg, 87.5 μιηοΐ), pyridin-3-ylboronic acid (16.1 mg, 131 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (3.57 mg, 4.38 μιηοΐ) and potassium carbonate (36.3 mg, 263 μιηοΐ) in N,N-dimethylformamide (75 μΐ), water (310 μΐ) and 1, 2 -dimethoxy ethane (440 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated overnight at 80°C. The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was evaporated and the residue was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 2.40 mg (99 % purity, 5 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.97 min; MS (ESIneg): m/z = 568 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 0.936 (1.08), 1.130 (9.59), 1.138 (9.72), 1.285 (9.86), 2.047 (1.28), 2.328 (1.82), 2.670 (1.96), 2.711 (1.15), 3.707 (14.24), 7.425 (4.59), 7.431 (4.46), 7.446 (5.06), 7.453 (5.00), 7.580 (3.71), 7.593 (4.12), 7.599 (3.92), 7.612 (4.05), 7.713 (4.32), 7.731 (3.65), 8.012 (9.05), 8.018 (8.84), 8.037 (12.96), 8.138 (3.85), 8.153 (3.71), 8.421 (16.00), 8.583 (9.05), 8.589 (8.71), 8.696 (5.94), 8.708 (5.74), 8.898 (7.43), 10.632 (8.37).
Example 95
ethyl 5 - {6-fluoro-3 - [3 - { [ 1 -(morpholin-4-yl)cyclopropane- 1 -carbonyl] amino } -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000211_0001
A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (50.0 mg, 87.5 μmol), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (48.5 mg, 175 μιηοΐ), [l,l '-bis-(diphenylphosphino)- ferrocenj-dichloropalladium (6.40 mg, 8.75 μιηοΐ) and sodium carbonate (37.1 mg, 350 μιηοΐ) in 1,4- dioxane (3.0 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. After cooling to rt, the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the crude material was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 2.40 mg (99 % purity, 4 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.24 min; MS (ESIpos): m/z = 642 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.93), 0.008 (1.72), 0.068 (0.50), 1.119 (1.53), 1.131 (4.11), 1.139 (4.39), 1.149 (2.01), 1.235 (0.64), 1.276 (2.05), 1.286 (4.35), 1.293 (3.77), 1.306 (1.50), 1.355 (7.36), 1.372 (16.00), 1.390 (7.64), 1.439 (0.72), 1.479 (0.67), 1.636 (0.72), 1.676 (0.72), 2.327 (0.96), 2.366 (0.79), 2.472 (6.40), 2.670 (1.05), 2.710 (0.93), 3.710 (6.11), 4.385 (2.27), 4.403 (7.16), 4.421 (7.19), 4.439 (2.34), 7.432 (2.32), 7.438 (2.34), 7.454 (2.48), 7.460 (2.63), 7.715 (1.91), 7.734 (1.89), 8.038 (4.11), 8.064 (3.96), 8.114 (3.80), 8.132 (3.82), 8.436 (8.76), 8.555 (3.39), 8.559 (3.73), 8.588 (4.61), 8.594 (4.61), 9.147 (3.77), 9.194 (5.01), 9.198 (5.23), 10.633 (4.30).
Example 96
N-{5-[7-(5-chloropyridin-3-yl)-6-fluoro-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l - (morpholin-4-yl)cyclopropane- 1 -carboxamide
Figure imgf000212_0001
A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (20.0 mg, 35.0 μmol), (5-chloropyridin-3-yl)boronic acid (11.0 mg, 70.0 μιηοΐ), [l, -bis-(diphenylphosphino)-ferrocen]-dichloropalladium (2.86 mg, 3.50 μιηοΐ) and sodium carbonate (14.8 mg, 140 μιηοΐ) in 1,4-dioxane (2.0 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. After cooling to rt, the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the crude material was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 5.60 mg (99 % purity, 26 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.28 min; MS (ESIpos): m/z = 604 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (3.52), 0.008 (3.44), 0.069 (1.15), 0.146 (0.49), 1.117 (2.78), 1.129 (7.67), 1.137 (8.38), 1.147 (3.88), 1.234 (0.87), 1.275 (3.74), 1.285 (8.25), 1.292 (7.02), 1.304 (2.92), 2.327 (1.28), 2.366 (0.98), 2.471 (11.36), 2.523 (3.58), 2.670 (1.45), 2.710 (1.09), 3.707 (10.98), 7.425 (4.34), 7.432 (4.23), 7.447 (4.75), 7.454 (4.89), 7.709 (3.58), 7.713 (3.71), 7.731 (3.28), 7.735 (2.98), 8.021 (6.61), 8.046 (6.50), 8.091 (6.96), 8.109 (6.91), 8.336 (5.52), 8.428 (16.00), 8.584 (8.74), 8.591 (8.68), 8.770 (7.78), 8.776 (7.70), 8.863 (7.86), 10.631 (7.89).
Example 97
N-{5-[6-fluoro-4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(4- methylpiperazin-1 -yl)cyclopropane-l -carboxamide
Figure imgf000213_0001
A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (60.0 mg, 95 % purity, 97.5 μιηοΐ), pyridin-3- ylboronic acid (18.0 mg, 146 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium- dichloromethane -complex (7.97 mg, 9.75 μιηοΐ) and potassium carbonate (40.4 mg, 293 μιηοΐ) ίη Ν,Ν- dimethylformamide (84 μΐ), water (350 μΐ) and 1,2-dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated overnight at 80°C. The reaction mixture was filtered through celite and the filter cake was washed with a mixture of dichloromethane/methanol 10: 1. The filtrate was evaporated and the residue was then submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 29.0 mg (99 % purity, 51 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.18 min; MS (ESIneg): m/z = 581 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.131 (4.54), 1.253 (4.60), 2.197 (16.00), 2.328 (1.90), 2.463 (6.70), 2.670 (1.93), 2.710 (1.06), 7.410 (2.19), 7.417 (2.06), 7.433 (2.51), 7.439 (2.29), 7.580 (1.77), 7.592 (1.80), 7.599 (1.90), 7.612 (1.77), 7.708 (2.09), 7.726 (1.71), 8.012 (4.19), 8.017 (4.22), 8.036 (5.86), 8.138 (1.74), 8.153 (1.67), 8.422 (8.21), 8.634 (4.57), 8.641 (4.41), 8.696 (2.61), 8.708 (2.61), 8.898 (3.19), 10.668 (3.96).
Example 98
ethyl 5 - {6-fluoro-3 - [3 - { [ 1 -(4-methylpiperazin- 1 -yl)cyclopropane- 1 -carbonyl] amino } -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000214_0001
A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (60.0 mg, 95 % purity, 97.5 μιηοΐ), ethyl 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (54.1 mg, 195 μmol), [1,1 '-bis- (diphenylphosphino)-ferrocen]-dichloropalladium (7.14 mg, 9.75 μιηοΐ) and sodium carbonate (41.4 mg, 390 μιηοΐ) in 1,4-dioxane (3.3 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. After cooling to rt, the reaction mixture was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 80:20 to provide 37.0 mg (95 % purity, 55 % yield) of the title product.
LC-MS (Method 6): Rt = 1.45 min; MS (ESIneg): m/z = 653 [M-H]"
Ή-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 0.008 (1.69), 1.189 (0.78), 1.202 (2.15), 1.209 (2.62), 1.220 (1.28), 1.242 (0.74), 1.259 (0.41), 1.317 (1.21), 1.328 (2.77), 1.335 (2.14), 1.348 (0.91), 1.435 (3.99), 1.453 (8.42), 1.470 (4.18), 1.571 (16.00), 2.339 (11.12), 2.441 (0.56), 4.449 (1.28), 4.466 (4.01), 4.484 (3.92), 4.502 (1.27), 7.178 (1.32), 7.185 (1.32), 7.200 (1.50), 7.207 (1.60), 7.458 (1.15), 7.480 (1.00), 7.909 (2.22), 7.926 (2.15), 8.113 (2.33), 8.125 (4.86), 8.138 (2.30), 8.583 (1.83), 8.586 (1.82), 8.778 (2.68), 8.784 (2.65), 9.061 (2.22), 9.304 (2.77), 9.309 (2.75), 10.709 (1.56).
Example 99
N-{5-[7-(5-chloropyridin-3-yl)-6-fluoro-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(4- methylpiperazin-1 -yl)cyclopropane-l -carboxamide
Figure imgf000215_0001
A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (850 mg, 1.45 mmol), (5-chloropyridin-3-yl)boronic acid (458 mg, 2.91 mmol), [l, -bis-(diphenylphosphino)-ferrocen]-dichloropalladium (119 mg, 145 μηιοΐ) and sodium carbonate (617 mg, 5.82 mmol) in 1,4-dioxane (14 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. After cooling to rt, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified twice by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 90: 10 followed by a preparative RP-HPLC 250x30mm with acetonitrile/water (0.1% formic acid) to afford 541 mg (99 % purity, 60 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.42 min; MS (ESIpos): m/z = 617 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.123 (4.57), 1.253 (4.57), 2.197 (16.00), 2.362 (3.87), 2.634 (3.16), 7.437 (2.46), 7.706 (2.11), 8.024 (3.16), 8.045 (3.16), 8.091 (2.99), 8.105 (3.69), 8.333 (3.16), 8.428 (7.56), 8.640 (4.22), 8.770 (4.22), 8.863 (4.04), 10.665 (4.04).
Example 100
N-{5-[8-fluoro-4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l-(morpholin- 4-yl)cyclopropane-l -carboxamide
Figure imgf000215_0002
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (210 mg, 368 μιηοΐ), pyridin-3-ylboronic acid (67.8 mg, 551 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane -complex (15.0 mg, 18.4 μιηοΐ) and potassium carbonate (152 mg, 1.10 mmol) in N,N-dimethylformamide (320 μΐ), water (1.3 ml) and 1 ,2-dimethoxyethane (1.8 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was combined with a second batch performed in the same scale and under the same conditions and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 90: 10 followed by a preparative RP-HPLC 220x50mm with acetonitrile/water (0.1% formic acid) to afford 170 mg (99 % purity, 40 % corrected yield) of the title compound.
LC-MS (Method 6): Rt = 1.91 min; MS (ESIpos): m/z = 570 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.82), -0.008 (6.93), 0.008 (6.72), 0.146 (0.75), 1.120 (3.26), 1.132 (9.15), 1.139 (10.15), 1.150 (4.73), 1.191 (0.45), 1.233 (0.52), 1.275 (4.38), 1.286 (9.97), 1.293 (8.36), 1.305 (3.41), 2.328 (0.65), 2.366 (0.80), 2.462 (9.48), 2.473 (13.62), 2.483 (11.16), 2.670 (0.61), 2.710 (0.75), 3.697 (9.61), 3.708 (13.41), 3.718 (9.56), 7.429 (4.90), 7.436 (4.88), 7.451 (5.53), 7.457 (5.64), 7.590 (3.54), 7.602 (3.74), 7.610 (3.82), 7.622 (3.89), 7.716 (4.10), 7.719 (4.19), 7.738 (3.67), 7.741 (3.45), 7.784 (3.58), 7.801 (4.38), 7.805 (4.68), 7.822 (4.08), 8.089 (6.61), 8.109 (5.85), 8.126 (3.48), 8.144 (3.22), 8.482 (16.00), 8.596 (9.07), 8.603 (9.03), 8.693 (4.94), 8.697 (4.94), 8.704 (4.95), 8.708 (4.71), 8.892 (6.31), 10.634 (9.28).
Example 101
ethyl 5 - { 8 -fluoro-3 - [3 - { [ 1 -(4-methylpiperazin- 1 -yl)cyclopropane- 1 -carbonyl] amino } -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000216_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (400 mg, 684 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (379 mg, 1.37 mmol), [l,l '-bis-(diphenylphosphino)- ferrocenj-dichloropalladium (55.9 mg, 68.4 μηιοΐ) and sodium carbonate (290 mg, 2.74 mmol) in 1,4- dioxane (11 ml) was degassed by passing argon through it for 5 min and the mixture was allowed to stir at 105°C overnight. After cooling to rt, the reaction mixture was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 85: 15 followed by a preparative RP-HPLC 220x50mm with acetonitrile/water (0.1% formic acid) to afford 253 mg (99 % purity, 56 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.38 min; MS (ESIneg): m/z = 653 [M-H]"
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.119 (1.70), 1.128 (4.71), 1.134 (4.92), 1.142 (2.35), 1.245 (2.30), 1.254 (5.11), 1.259 (4.37), 1.270 (1.79), 1.359 (7.66), 1.374 (16.00), 1.388 (7.73), 2.217 (6.93), 2.362 (0.56), 2.474 (5.42), 2.635 (0.50), 4.392 (2.44), 4.407 (7.38), 4.421 (7.32), 4.435 (2.30), 7.427 (2.38), 7.432 (2.35), 7.444 (2.57), 7.449 (2.64), 7.713 (2.25), 7.728 (2.01), 7.855 (1.78), 7.871 (2.33), 7.885 (1.86), 8.106 (3.81), 8.123 (3.22), 8.495 (9.01), 8.546 (3.96), 8.639 (2.52), 9.138 (4.04), 9.189 (5.29), 9.193 (5.06), 10.647 (1.87).
Example 102
N-[5- {7-[5-(hydroxymethyl)pyridin-3-yl]-4-oxoquinazolin-3(4H)-yl} -2-(trifluoromethoxy)phenyl]-l- (morpholin-4-yl)cyclopropane- 1 -carboxamide
Figure imgf000217_0001
A mixture of l-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropane-l -carboxamide (114 mg, 50 % purity, 94.9 μιηοΐ), (5-bromopyridin-3-yl)methanol (28.2 mg, 95 % purity, 142 μιηοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (3.88 mg, 4.75 μιηοΐ) and potassium carbonate (26.2 mg, 190 μιηοΐ) in N,N-dimethylformamide (83 μΐ), water (330 μΐ) and 1,2- dimethoxyethane (460 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was filtered through celite and the filter cake was washed with a mixture of dichloromethane/methanol 10: 1. The filtrate was evaporated and the residue was then purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 90: 10 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% formic acid) to afford 39.4 mg (99 %> purity, 71 %> yield) of the title compound. LC-MS (Method 6): Rt = 1.61 min; MS (ESIpos): m/z = 582 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.74), -0.008 (7.20), 0.008 (7.41), 0.146 (0.74), 1.118 (2.69), 1.130 (7.64), 1.138 (8.46), 1.148 (3.95), 1.231 (0.45), 1.273 (3.69), 1.283 (8.25), 1.290 (7.04), 1.303 (2.82), 2.366 (0.66), 2.472 (11.89), 2.483 (9.91), 2.710 (0.61), 3.708 (11.68), 4.654 (10.28), 4.669 (10.60), 5.413 (3.64), 5.427 (7.22), 5.442 (3.40), 7.430 (4.16), 7.436 (4.11), 7.452 (4.51), 7.458 (4.80), 7.703 (3.51), 7.707 (3.64), 7.725 (3.11), 7.728 (2.95), 7.974 (3.98), 7.979 (4.19), 7.995 (4.38), 8.000 (4.82), 8.094 (7.96), 8.098 (7.75), 8.180 (6.70), 8.292 (7.20), 8.313 (6.25), 8.429 (16.00), 8.576 (7.86), 8.583 (7.99), 8.623 (6.54), 8.627 (6.59), 8.951 (6.77), 8.956 (6.83), 10.628 (7.67).
Example 103
N-[5- {7-[5-(hydroxymethyl)pyridin-3-yl]-4-oxoquinazolin-3(4H)-yl} -2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-1 -yl)cyclopropane-l -carboxamide
Figure imgf000218_0001
A mixture of 1 -(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropane-l -carboxamide (134 mg, 62 % purity, 135 μιηοΐ), (5-bromopyridin-3-yl)methanol (40.2 mg, 95 % purity, 203 μιηοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (5.53 mg, 6.77 μιηοΐ) and potassium carbonate (37.4 mg, 271 μιηοΐ) in N,N-dimethylformamide (120 μΐ), water (480 μΐ) and 1,2- dimethoxyethane (650 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 80:20 (+ 0.2% ammonia) followed by a preparative RP-HPLC 125x40mm with acetonitrile/water (neutral conditions) to afford 34.5 mg (92 % purity, 39 % yield) and 25.0 mg (99 % purity, 31 % yield) of the title compound.
LC-MS (Method 6): Rt = 0.94 min; MS (ESIneg): m/z = 593 [M-H]"
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (0.50), 1.110 (1.40), 1.123 (3.74), 1.130 (4.19), 1.140 (1.97), 1.242 (1.97), 1.252 (4.17), 1.260 (3.36), 1.272 (1.40), 1.402 (1.09), 2.198 (16.00), 2.327 (0.49), 2.366 (0.69), 2.670 (0.43), 2.710 (0.41), 4.661 (5.62), 5.430 (1.20), 7.416 (2.08), 7.422 (2.07), 7.438 (2.30), 7.444 (2.36), 7.697 (1.73), 7.701 (1.77), 7.719 (1.55), 7.723 (1.44), 7.974 (2.05), 7.978 (2.15), 7.994 (2.23), 7.999 (2.46), 8.093 (4.12), 8.097 (3.92), 8.180 (3.46), 8.292 (3.94), 8.312 (3.43), 8.430 (8.25), 8.622 (3.34), 8.628 (6.44), 8.634 (3.93), 8.950 (3.59), 8.956 (3.54), 10.665 (3.86).
Example 104
N-{5-[8-fluoro-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(4- methylpiperazin- 1 -yl)cyclopropane- 1 -carboxamide
Figure imgf000219_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (150 mg, 257 μηιοΐ), (2-fluorophenyl)boronic acid (53.9 mg, 385 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (10.5 mg, 12.8 μηιοΐ) and potassium carbonate (106 mg, 770 μηιοΐ) in N,N- dimethylformamide (230 μΐ), water (970 μΐ) and 1,2-dimethoxyethane (1.4 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 97:3 to 80:20 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% formic acid) to afford 86.0 mg (99 % purity, 56 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.50 min; MS (ESIpos): m/z = 600 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (1.70), -0.007 (16.00), 0.006 (15.92), 0.042 (0.66), 0.116 (1.86), 1.117 (1.70), 1.127 (4.55), 1.133 (5.00), 1.142 (2.32), 1.247 (2.23), 1.255 (5.21), 1.261 (4.34), 1.271 (1.82), 2.205 (5.58), 2.363 (1.41), 2.636 (1.41), 3.369 (0.66), 7.393 (1.57), 7.406 (4.84), 7.418 (3.18), 7.422 (7.24), 7.435 (2.94), 7.441 (3.60), 7.580 (2.32), 7.593 (3.56), 7.609 (2.15), 7.640 (1.70), 7.656 (2.07), 7.669 (1.82), 7.719 (2.19), 7.734 (2.07), 8.078 (3.84), 8.095 (3.43), 8.468 (9.84), 8.646 (2.07), 10.667 (1.65).
Example 105
N-{5-[8-fluoro-4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-l -(4- methylpiperazin- 1 -yl)cyclopropane-l -carboxamide
Figure imgf000220_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (150 mg, 257 μmol), pyridin-3-ylboronic acid (47.3 mg, 385 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (10.5 mg, 12.8 μηιοΐ) and potassium carbonate (106 mg, 770 μηιοΐ) in N,N-dimethylformamide (220 μΐ), water (920 μΐ) and 1 ,2-dimethoxyethane (1.3 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The solvent was evaporated under reduced pressure and the crude material was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 90: 10 followed by a second chromatography over NH-modified silica gel (Biotage® SNAP KP-NH Cartridge) eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 to afford 99.0 mg (99 % purity, 66 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.09 min; MS (ESIneg): m/z = 581 [M-H]"
Ή-ΝΜΡν (500 MHz, CHLOROFORM-d) δ [ppm]: 0.071 (0.56), 1.192 (1.50), 1.202 (4.12), 1.208 (4.33), 1.217 (1.99), 1.321 (2.07), 1.330 (4.75), 1.336 (3.78), 1.346 (1.44), 1.623 (5.00), 2.344 (16.00), 2.669 (0.49), 5.302 (11.86), 7.167 (2.12), 7.172 (2.06), 7.185 (2.29), 7.190 (2.26), 7.459 (1.82), 7.468 (3.36), 7.475 (1.84), 7.485 (3.05), 7.599 (1.62), 7.613 (1.89), 7.616 (1.90), 7.629 (1.70), 8.002 (1.48), 8.017 (1.41), 8.194 (7.01), 8.214 (2.73), 8.230 (2.57), 8.702 (2.18), 8.705 (2.22), 8.711 (2.23), 8.714 (2.10), 8.793 (4.09), 8.798 (3.96), 8.915 (2.85), 10.714 (2.43).
Example 106
N- {2-(difluoromethoxy)-5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]phenyl} -1 -(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000221_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (120 mg, 224 μιηοΐ), (2-fluorophenyl)boronic acid (47.0 mg, 336 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (9.15 mg, 11.2 μιηοΐ) and potassium carbonate (92.9 mg, 672 μιηοΐ) in N,N-dimethylformamide (200 μΐ), water (850 μΐ) and 1,2-dimethoxyethane (1.3 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 98:2 to 20:80 to afford 108 mg (99 % purity, 88 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.48 min; MS (ESIpos): m/z = 551 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.111 (0.89), 1.119 (2.59), 1.124 (2.53), 1.131 (1.11), 1.252 (1.16), 1.259 (2.70), 1.264 (2.31), 1.272 (0.87), 3.320 (16.00), 7.347 (1.14), 7.352 (1.11), 7.362 (1.32), 7.366 (1.33), 7.375 (0.84), 7.387 (2.59), 7.400 (2.02), 7.418 (0.82), 7.505 (2.56), 7.513 (0.59), 7.516 (0.59), 7.522 (1.98), 7.538 (0.66), 7.628 (0.86), 7.688 (0.62), 7.701 (1.19), 7.714 (0.60), 7.783 (1.20), 7.796 (1.26), 7.899 (2.37), 8.270 (2.14), 8.284 (1.98), 8.381 (4.58), 8.549 (2.29), 8.553 (2.24), 10.694 (2.35).
Example 107
N-[2-(difluoromethoxy)-5-(4-oxo-7-phenylquinazolin-3(4H)-yl)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000221_0002
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (120 mg, 224 μιηοΐ), phenylboronic acid (41.0 mg, 336 μιηοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (9.15 mg, 11.2 μmol) and potassium carbonate (92.9 mg, 672 μιηοΐ) in N,N-dimethylformamide (200 μΐ), water (850 μΐ) and 1,2- dimethoxyethane (1.3 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 98:2 to 20:80 to afford 82.0 mg (99 % purity, 69 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.22 min; MS (ESIpos): m/z = 533 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.07), -0.008 (9.42), 0.008 (10.34), 0.146 (1.07), 1.104 (2.44), 1.116 (6.52), 1.124 (7.33), 1.134 (3.49), 1.249 (3.33), 1.259 (7.38), 1.266 (6.07), 1.279 (2.55), 2.328 (1.07), 2.366 (1.02), 2.461 (8.99), 2.523 (4.54), 2.670 (1.07), 2.674 (0.78), 2.710 (0.94), 3.721 (6.95), 3.731 (10.01), 3.741 (7.06), 7.318 (3.52), 7.342 (3.76), 7.349 (3.76), 7.364 (4.46), 7.370 (4.59), 7.461 (1.40), 7.474 (1.15), 7.480 (4.67), 7.485 (1.58), 7.502 (14.04), 7.523 (4.54), 7.534 (5.99), 7.554 (8.67), 7.571 (3.73), 7.686 (3.33), 7.851 (8.05), 7.869 (7.73), 7.872 (5.42), 7.921 (3.68), 7.925 (3.97), 7.941 (4.03), 7.946 (4.51), 8.008 (7.44), 8.012 (6.77), 8.254 (7.14), 8.275 (6.26), 8.373 (16.00), 8.539 (7.38), 8.546 (7.28), 10.691 (6.63).
Example 108
N-{5-[7-(5-cyanopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(difluoromethoxy)phenyl} -l-(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000222_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (120 mg, 224 μιηοΐ), (5-cyanopyridin-3-yl)boronic acid (49.7 mg, 336 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (9.15 mg, 11.2 μιηοΐ) and potassium carbonate (92.9 mg, 672 μιηοΐ) in N,N-dimethylformamide (200 μΐ), water (850 μΐ) and 1,2 -dimethoxyethane (1.3 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 98:2 to 0:100 to afford 40.0 mg (98 % purity, 31 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.27 min; MS (ESIpos): m/z = 559 [M+H]+
Ή- MR (600 MHz, DMSO-d6) δ [ppm] : 1.116 (11.12), 1.262 (11.28), 2.385 (3.35), 2.424 (4.11), 2.461 (15.70), 2.614 (3.35), 2.653 (3.05), 3.288 (4.72), 3.351 (5.49), 3.359 (3.96), 3.731 (16.00), 7.359 (4.27),
7.373 (5.03), 7.383 (3.66), 7.506 (9.75), 7.523 (6.10), 7.628 (3.20), 8.060 (5.03), 8.073 (5.33), 8.241 (10.06), 8.301 (7.92), 8.316 (6.86), 8.414 (15.54), 8.550 (8.69), 8.554 (8.69), 8.881 (9.60), 9.111 (9.45),
9.374 (9.14), 10.696 (9.75).
Example 109
N- {2-(difluoromethoxy)-5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]phenyl} -2-(morpholin-4- yl)propanamide (Enantiomer 1)
Figure imgf000223_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (enantiomer 1) (150 mg, 287 μιηοΐ), (2-fluorophenyl)boronic acid (60.2 mg, 430 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (11.7 mg, 14.3 μιηοΐ) and potassium carbonate (119 mg, 860 μιηοΐ) in N,N-dimethylformamide (250 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.6 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 85: 15 followed by a preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid) to afford 45.0 mg (99 % purity, 29 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.24 min; MS (ESIpos): m/z = 539 [M+H]+
Ή- MR (600 MHz, DMSO-d6) δ [ppm] : 1.198 (16.00), 1.210 (16.00), 2.426 (0.53), 2.565 (6.91), 2.573
(4.64) , 2.585 (2.47), 2.655 (0.47), 3.295 (0.70), 3.357 (0.90), 3.370 (1.74), 3.382 (4.54), 3.393 (4.41), 3.405 (1.37), 3.687 (12.03), 7.320 (2.81), 7.362 (3.34), 7.366 (3.34), 7.376 (6.05), 7.390 (7.92), 7.403
(6.65) , 7.421 (2.81), 7.442 (5.75), 7.486 (5.98), 7.500 (4.68), 7.518 (1.37), 7.529 (2.51), 7.539 (2.30), 7.553 (0.97), 7.564 (2.67), 7.693 (2.07), 7.705 (3.91), 7.718 (1.97), 7.788 (3.87), 7.801 (4.08), 7.904 (7.82), 8.278 (6.48), 8.292 (6.01), 8.388 (13.19), 8.454 (6.75), 8.458 (6.58), 10.110 (7.48). Example 110
N-{2-(difluoromethoxy)-5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]phenyl}-2-(morpholin-4- yl)propanamide (Enantiomer 2)
Figure imgf000224_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (enantiomer 2) (150 mg, 287 μιηοΐ), (2-fluorophenyl)boronic acid (60.2 mg, 430 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (11.7 mg, 14.3 μιηοΐ) and potassium carbonate (119 mg, 860 μιηοΐ) in N,N-dimethylformamide (250 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.6 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 80:20 to 0: 100 to afford 123 mg (99 % purity, 79 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.25 min; MS (ESIpos): m/z = 539 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.199 (15.93), 1.210 (16.00), 2.426 (0.50), 2.525 (2.16), 2.557 (4.14), 2.565 (6.13), 2.573 (4.11), 2.585 (2.16), 2.592 (1.26), 2.655 (0.50), 3.293 (0.43), 3.303 (0.90), 3.359 (0.76), 3.370 (1.48), 3.382 (4.54), 3.393 (4.36), 3.405 (1.26), 3.687 (10.13), 7.320 (2.88), 7.362 (3.32), 7.366 (3.35), 7.376 (5.84), 7.380 (4.68), 7.390 (7.57), 7.403 (6.49), 7.422 (2.59), 7.442 (5.95), 7.486 (5.84), 7.500 (4.54), 7.519 (1.23), 7.528 (2.20), 7.541 (1.95), 7.551 (0.90), 7.564 (2.70), 7.692 (1.80), 7.705 (3.53), 7.718 (1.84), 7.788 (3.60), 7.802 (3.78), 7.904 (7.14), 8.279 (6.74), 8.292 (6.20), 8.389 (14.27), 8.454 (6.77), 8.458 (6.74), 10.110 (6.99).
Example 111
ethyl 5-{3-[4-(methoxymethyl)-3- {[l-(morpholin-4-yl)cyclopropane-l-carbonyl]amino}phenyl]-4-oxo- 3 ,4-dihydroquinazolin-7-yl} pyridine-3 -carboxylate H 3C
O-C H 3
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(morpholin-4-yl)cyclopropane-l-carboxamide (92.6 mg, 69 % purity, 114 μιηοΐ), ethyl 5-bromopyridine-3-carboxylate (35.4 mg, 154 μιηοΐ), [l,l-bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (4.65 mg, 5.70 μιηοΐ) and potassium carbonate (31.5 mg, 228 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1, 2 -dimethoxy ethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was diluted in water and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 99: 1 to 90: 10 followed by a preparative RP- HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 16.9 mg (96 % purity, 24 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.91 min; MS (ESIpos): m/z = 584 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.085 (1.11), 1.097 (2.96), 1.104 (3.35), 1.113 (1.71), 1.221 (3.35), 1.227 (2.90), 1.240 (1.18), 1.367 (4.01), 1.385 (8.08), 1.403 (4.03), 3.278 (0.73), 3.355 (16.00), 3.725 (4.25), 3.736 (5.87), 3.746 (4.02), 4.392 (1.32), 4.410 (3.83), 4.427 (3.76), 4.445 (1.24), 4.669 (6.57), 7.278 (1.43), 7.283 (1.43), 7.298 (1.61), 7.303 (1.59), 7.544 (2.39), 7.564 (2.07), 8.033 (1.45), 8.052 (1.69), 8.183 (3.13), 8.309 (2.37), 8.329 (2.04), 8.374 (2.95), 8.378 (2.93), 8.413 (4.96), 8.637 (2.72), 9.163 (2.78), 9.166 (2.67), 9.315 (2.76), 9.320 (2.65), 10.737 (2.78).
Example 112
N- {2-(methoxymethyl)-5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]phenyl} -1 -(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000226_0001
A mixture of N-{2-(methoxymethyl)-5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]phenyl} -l -(morpholin-4-yl)cyclopropane-l-carboxamide (92.6 mg, 69 % purity, 114 μιηοΐ), 3-bromopyridine (24.3 mg, 154 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.65 mg, 5.70 μιηοΐ) and potassium carbonate (31.5 mg, 228 μιηοΐ) in N,N-dimethylformamide (100 μΐ), water (400 μΐ) and 1,2-dimethoxyethane (550 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 3 h. The reaction mixture was diluted in water and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 99: 1 to 90: 10 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 24.4 mg (99 % purity, 42 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.55 min; MS (ESIpos): m/z = 512 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.083 (0.88), 1.096 (2.40), 1.103 (2.77), 1.113 (1.33), 1.210 (1.27), 1.220 (2.75), 1.227 (2.15), 1.239 (0.87), 3.278 (0.58), 3.353 (16.00), 3.724 (3.23), 3.735 (4.43), 3.746 (3.00), 4.668 (5.83), 7.272 (1.25), 7.277 (1.23), 7.292 (1.38), 7.297 (1.37), 7.541 (2.16), 7.554 (1.20), 7.562 (2.12), 7.574 (1.13), 7.586 (1.12), 7.979 (1.19), 7.983 (1.18), 8.000 (1.35), 8.004 (1.37), 8.111 (2.50), 8.115 (2.29), 8.277 (1.22), 8.284 (2.53), 8.292 (0.89), 8.296 (1.19), 8.305 (2.11), 8.369 (2.56), 8.374 (2.53), 8.395 (4.80), 8.666 (1.38), 8.670 (1.33), 8.678 (1.39), 8.681 (1.28), 9.074 (2.02), 9.080 (2.01), 10.736 (2.29).
Example 113
N-{5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(6-oxa-3- azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane-l -carboxamide
Figure imgf000227_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l -carboxamide (37.0 mg, 97 % purity, 63.5 μηιοΐ), (5- fluoropyridin-3-yl)boronic acid (30.2 mg, 40 % purity, 85.7 μηιοΐ), [l,l-bis-(diphenylphosphino)- ferrocenj-dichloropalladium-dichloromethane-complex (5.18 mg, 6.35 μmol) and potassium carbonate (17.5 mg, 127 μηιοΐ) in N,N-dimethylformamide (56 μΐ), water (220 μΐ) and 1, 2 -dimethoxy ethane (310 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 6.60 mg (99 % purity, 18 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 582 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.270 (12.86), 1.309 (12.24), 2.289 (4.39), 2.311 (4.39), 2.367 (16.00), 2.669 (3.76), 2.710 (16.00), 2.933 (5.65), 2.961 (10.67), 3.004 (13.18), 3.033 (6.90), 3.054 (4.08), 3.074 (3.76), 4.524 (10.35), 4.539 (10.04), 7.445 (4.39), 7.467 (5.02), 7.674 (5.02), 7.694 (4.08), 8.037 (4.71), 8.057 (5.65), 8.199 (10.04), 8.288 (8.16), 8.308 (9.73), 8.326 (4.71), 8.440 (14.12), 8.520 (8.16), 8.685 (8.47), 8.691 (8.47), 8.992 (9.10), 9.993 (5.96).
Example 114
l-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N- {5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide
Figure imgf000227_0002
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l -carboxamide (37.0 mg, 97 % purity, 63.5 μιηοΐ), pyridin- 3-ylboronic acid (31.9 mg, 33 % purity, 85.7 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (5.18 mg, 6.35 μιηοΐ) and potassium carbonate (17.5 mg, 127 μιηοΐ) in N,N-dimethylformamide (56 μΐ), water (220 μΐ) and 1,2-dimethoxyethane (310 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by two consecutive preparative RP-HPLC 125x30mm with acetonitrile/water (first with 0.2% ammonia and then neutral conditions) to afford 13.1 mg (97 % purity, 36 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.76 min; MS (ESIpos): m/z = 564 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.271 (9.56), 1.309 (9.37), 2.291 (2.93), 2.328 (3.32), 2.367 (7.02), 2.670 (3.12), 2.710 (7.02), 2.933 (3.90), 2.962 (8.20), 3.004 (10.34), 3.033 (5.07), 3.054 (2.73), 3.075 (2.73), 4.525 (7.80), 4.540 (7.61), 7.438 (3.90), 7.444 (3.51), 7.460 (4.49), 7.466 (4.68), 7.558 (2.93), 7.570 (3.32), 7.577 (3.12), 7.589 (3.51), 7.674 (4.10), 7.693 (2.73), 7.985 (4.29), 8.011 (4.68), 8.117 (8.39), 8.121 (8.20), 8.288 (8.98), 8.309 (7.80), 8.431 (16.00), 8.513 (7.22), 8.519 (7.61), 8.672 (5.07), 8.680 (5.07), 9.082 (6.63), 9.994 (5.07).
Example 115
N-{5-[7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(3-oxa-7- azabicyclo[3.3.1]nonan-7-yl)propanamide (racemate)
Figure imgf000228_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(3-oxa-7- azabicyclo[3.3.1]nonan-7-yl)propanamide (27.8 mg, 47.8 μιηοΐ), (5-fluoropyridin-3-yl)boronic acid (10.1 mg, 71.7 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (1.95 mg, 2.39 μιηοΐ) and potassium carbonate (19.8 mg, 143 μιηοΐ) in N,N- dimethylformamide (41 μΐ), water (170 μΐ) and 1,2-dimethoxyethane (240 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 85: 15 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% formic acid) to afford 6.00 mg (90 % purity, 19 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.31 min; MS (ESIpos): m/z = 598 [M+H]+
Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 0.805 (1.29), 1.096 (1.63), 1.162 (16.00), 1.176 (15.85), 1.235 (0.44), 1.615 (1.85), 1.640 (2.15), 1.715 (3.81), 1.830 (2.32), 1.854 (1.88), 2.362 (0.63), 2.639 (2.73), 2.660 (2.94), 2.787 (3.08), 2.808 (2.35), 2.865 (3.30), 2.886 (4.40), 2.964 (3.23), 2.985 (2.09), 3.349 (3.08), 3.363 (5.39), 3.377 (4.95), 3.391 (1.73), 3.447 (2.51), 3.703 (2.60), 3.725 (3.69), 3.737 (2.88), 3.760 (3.19), 3.817 (3.53), 3.840 (2.51), 3.909 (3.35), 3.931 (2.61), 7.457 (3.54), 7.462 (3.49), 7.474 (4.09), 7.479 (4.13), 7.624 (3.68), 7.640 (3.02), 8.036 (3.77), 8.039 (3.77), 8.053 (4.10), 8.056 (4.25), 8.198 (7.83), 8.201 (7.46), 8.287 (7.84), 8.294 (10.26), 8.303 (3.96), 8.311 (6.74), 8.323 (3.24), 8.456 (14.34), 8.684 (6.60), 8.690 (6.30), 8.992 (6.98), 10.511 (7.05).
Example 116
N-{5-[7-(5-chloropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(difluoromethoxy)phenyl} -l -(4- methylpiperazin- 1 -yl)cyclopropane- 1 -carboxamide
Figure imgf000229_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (65.0 mg, 119 μιηοΐ), (5-chloropyridin-3-yl)boronic acid (37.3 mg, 237 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (4.84 mg, 5.93 μιηοΐ) and potassium carbonate (49.1 mg, 356 μιηοΐ) in N,N- dimethylformamide (100 μΐ), water (430 μΐ) and 1,2-dimethoxyethane (600 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C overnight. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% formic acid) to afford 2.60 mg (95 % purity, 4 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.30 min; MS (ESIpos): m/z = 581 [M+H]+ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (4.31), 0.146 (3.38), 1.112 (5.85), 1.229 (6.46), 2.209 (16.00), 2.327 (14.77), 2.366 (8.00), 2.669 (16.00), 2.710 (7.38), 7.366 (2.77), 7.501 (6.15), 8.050 (3.38), 8.193 (6.46), 8.279 (4.92), 8.300 (4.62), 8.404 (9.54), 8.480 (5.23), 8.569 (4.92), 8.726 (4.31), 9.056 (5.54), 10.710 (4.31). Example 117
propan-2-yl 5- {3-[3-{[l -(morpholin-4-yl)cyclopropane-l -carbonyl] amino} -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate
Figure imgf000230_0001
A mixture of l-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropane-l -carboxamide (180 mg, 72 % purity, 216 μιηοΐ), propan-2-yl 5-bromopyridine-3-carboxylate (72.6 mg, 98 % purity, 291 μιηοΐ), [1,1- bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (8.81 mg, 10.8 μιηοΐ) and potassium carbonate (59.7 mg, 432 μιηοΐ) in N,N-dimethylformamide (190 μΐ), water (760 μΐ) and 1 ,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by a preparative RP- HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 76.8 mg (99 % purity, 56 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 638 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.20), 1.119 (0.97), 1.131 (2.68), 1.139 (2.93), 1.149 (1.37), 1.234 (0.49), 1.274 (1.28), 1.285 (2.87), 1.292 (2.46), 1.304 (0.98), 1.380 (15.98), 1.395 (16.00), 2.473 (4.33), 3.709 (4.14), 5.202 (0.43), 5.218 (1.15), 5.233 (1.51), 5.249 (1.11), 5.264 (0.42), 7.435 (1.33), 7.442 (1.32), 7.457 (1.50), 7.464 (1.54), 7.709 (1.27), 7.728 (1.08), 8.032 (1.33), 8.037 (1.37), 8.053 (1.48), 8.057 (1.59), 8.184 (2.80), 8.187 (2.72), 8.311 (2.57), 8.332 (2.18), 8.448 (5.32), 8.584 (2.59), 8.590 (2.59), 8.610 (1.63), 8.615 (2.85), 8.620 (1.72), 9.150 (2.53), 9.155 (2.50), 9.307 (2.77), 9.312 (2.76), 10.630 (2.70). Example 118
methyl 5- {3-[3-{[l -(morpholin-4-yl)cyclopropane- 1 -carbonyl] amino } -4-(trifluoromethoxy)phenyl] -4- oxo-3,4-dihydroquinazolin-7-yl}pyridine-2-carboxylate
Figure imgf000231_0001
A mixture of l-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropane-l -carboxamide (85.0 mg, 62 % purity, 87.8 μηιοΐ), methyl 5-bromopyridine-2-carboxylate (26.1 mg, 98 % purity, 118 μηιοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (3.58 mg, 4.39 μηιοΐ) and potassium carbonate (24.3 mg, 176 μηιοΐ) in N,N-dimethylformamide (77 μΐ), water (310 μΐ) and 1,2- dimethoxyethane (420 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 90: 10 followed by a preparative RP- HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 12.7 mg (99 % purity, 24 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.93 min; MS (ESIpos): m/z = 610 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.068 (1.19), 1.029 (0.89), 1.137 (4.83), 1.285 (4.99), 2.327 (1.60), 2.367 (1.08), 2.670 (1.82), 2.711 (1.00), 3.708 (7.89), 3.934 (16.00), 7.442 (2.22), 7.464 (2.44), 7.709 (2.47), 7.728 (1.93), 8.055 (2.03), 8.074 (2.33), 8.186 (2.98), 8.214 (4.75), 8.317 (3.47), 8.338 (3.01), 8.450 (7.38), 8.480 (2.22), 8.506 (2.06), 8.582 (4.04), 8.588 (3.91), 9.230 (3.55), 10.629 (4.12).
Example 119
methyl 3 -fluoro-4- {3 -[3- { [ 1 -(morpholin-4-yl)cyclopropane-l -carbonyl] amino} -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}benzoate
Figure imgf000232_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (40.0 mg, 98 % purity, 70.8 μιηοΐ), [2-fluoro-4- (methoxycarbonyl)phenyl]boronic acid (19.5 mg, 97 % purity, 95.6 μιηοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (2.89 mg, 3.54 μιηοΐ) and potassium carbonate (19.6 mg, 142 μιηοΐ) in N,N-dimethylformamide (62 μΐ), water (250 μΐ) and 1,2- dimethoxyethane (340 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 90: 10 followed by a preparative RP- HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 15.9 mg (99 % purity, 36 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.35 min; MS (ESIpos): m/z = 627 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.68), -0.008 (4.26), 0.008 (4.37), 0.146 (0.61), 1.118 (1.15), 1.130 (3.00), 1.138 (3.38), 1.149 (1.60), 1.234 (0.95), 1.283 (3.36), 2.327 (0.95), 2.367 (0.86), 2.472 (5.16), 2.669 (0.90), 2.710 (0.95), 3.708 (4.69), 3.919 (16.00), 7.428 (1.76), 7.435 (1.67), 7.450 (1.94), 7.456 (1.94), 7.709 (1.69), 7.730 (1.31), 7.824 (1.65), 7.845 (1.80), 7.870 (2.01), 7.878 (2.82), 7.897 (3.97), 7.935 (2.64), 7.968 (3.45), 8.302 (3.27), 8.323 (3.02), 8.433 (7.28), 8.579 (3.45), 8.586 (3.54), 10.628 (3.11).
Example 120
N-{5-[7-(2-methylphenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(morpholin-4- yl)propanamide (racemate)
Figure imgf000233_0001
A mixture of 2-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (100 mg, 69 % purity, 117 μηιοΐ), 1- bromo-2-methylbenzene (19 μΐ, 99 % purity, 160 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (4.79 mg, 5.86 μηιοΐ) and potassium carbonate (32.4 mg, 235 μηιοΐ) in N,N-dimethylformamide (100 μΐ), water (410 μΐ) and 1,2-dimethoxyethane (570 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 90: 10 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 52.8 mg (98 % purity, 80 % yield) of the title compound.
LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 553 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.201 (7.16), 1.218 (7.27), 2.285 (16.00), 2.524 (1.45), 2.569 (3.69), 2.580 (2.04), 2.598 (0.79), 2.608 (0.48), 3.385 (0.63), 3.403 (1.98), 3.420 (1.93), 3.438 (0.56), 3.660 (5.67), 7.306 (0.70), 7.315 (2.12), 7.321 (3.37), 7.335 (2.06), 7.358 (2.83), 7.365 (3.84), 7.371 (2.91), 7.443 (1.64), 7.449 (1.58), 7.465 (1.89), 7.471 (1.88), 7.581 (1.74), 7.585 (1.84), 7.602 (1.79), 7.606 (1.95), 7.675 (5.03), 7.678 (4.91), 7.697 (1.36), 8.243 (3.01), 8.263 (2.81), 8.408 (6.46), 8.425 (3.12), 8.431 (2.99), 10.101 (3.22).
Example 121
N-{5-[7-(3-methylphenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l -(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000234_0001
A mixture of l-(morpholin-4-yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropane-l -carboxamide (95.0 mg, 64 % purity, 101 μιηοΐ), l-bromo-3-methylbenzene (17 μΐ, 98 % purity, 140 μιηοΐ), [1,1-bis- (diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (4.13 mg, 5.06 μιηοΐ) and potassium carbonate (28.0 mg, 203 μιηοΐ) in N,N-dimethylformamide (89 μΐ), water (360 μΐ) and 1,2- dimethoxyethane (490 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 1 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 90: 10 followed by a preparative RP- HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 35.9 mg (99 % purity, 63 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.48 min; MS (ESIpos): m/z = 565 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.25), 0.008 (1.32), 1.117 (1.40), 1.130 (3.93), 1.137 (4.45), 1.147 (2.09), 1.233 (0.55), 1.271 (1.92), 1.282 (4.33), 1.289 (3.70), 1.302 (1.49), 2.073 (2.06), 2.366 (0.41), 2.407 (0.49), 2.425 (16.00), 2.470 (6.02), 2.481 (4.82), 3.707 (5.97), 7.283 (1.58), 7.302 (2.05), 7.413 (1.88), 7.423 (2.29), 7.432 (3.87), 7.445 (2.52), 7.451 (4.01), 7.630 (1.96), 7.650 (1.67), 7.681 (3.31), 7.698 (1.84), 7.702 (1.84), 7.720 (1.60), 7.724 (1.47), 7.909 (1.98), 7.913 (2.09), 7.930 (2.16), 7.934 (2.38), 7.993 (4.05), 7.997 (3.69), 8.245 (3.73), 8.266 (3.25), 8.402 (7.71), 8.568 (3.74), 8.575 (3.69), 10.625 (3.95). Example 122
N-{5-[7-(2-methylphenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(4- methylpiperazin-1 -yl)propanamide (racemate)
Figure imgf000235_0001
A mixture of 2-(4-methylpiperazin-l -yl)-N- {5-[4-oxo-7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}propanamide (340 mg, 53 % purity, 300 μηιοΐ), 1- bromo-2-methylbenzene (69.3 mg, 405 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (24.5 mg, 30.0 μηιοΐ) and potassium carbonate (82.9 mg, 600 μηιοΐ) in N,N-dimethylformamide (270 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.5 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 90: 10 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to afford 110 mg (98 % purity, 64 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 566 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.75), 0.008 (0.78), 1.185 (6.82), 1.203 (6.94), 2.183 (13.01), 2.285 (16.00), 2.328 (0.45), 2.333 (0.43), 2.367 (0.77), 2.407 (0.93), 2.524 (1.09), 3.403 (0.59), 3.421 (1.95), 3.438 (1.89), 3.456 (0.52), 7.306 (0.65), 7.315 (1.97), 7.320 (3.04), 7.324 (2.88), 7.329 (1.81), 7.335 (1.91), 7.339 (1.09), 7.358 (2.65), 7.365 (3.56), 7.371 (2.72), 7.376 (1.87), 7.423 (1.61), 7.430 (1.60), 7.445 (1.82), 7.451 (1.87), 7.581 (1.70), 7.585 (1.81), 7.602 (1.74), 7.606 (1.95), 7.674 (4.49), 7.678 (4.31), 7.696 (1.24), 7.700 (1.16), 8.242 (2.93), 8.262 (2.74), 8.410 (6.31), 8.510 (2.77), 8.516 (2.74), 10.158 (2.96).
Example 123
N-{2-(difluoromethoxy)-5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]phenyl}-2-(morpholin-4- yl)propanamide (enantiomer 1)
Figure imgf000235_0002
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (enantiomer 1) (150 mg, 287 μιηοΐ), pyridin-3-ylboronic acid (52.8 mg, 430 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (11.7 mg, 14.3 μιηοΐ) and potassium carbonate (119 mg, 860 μιηοΐ) in N,N-dimethylformamide (250 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.6 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by a preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid) to afford 89.8 mg (97 % purity, 58 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.62 min; MS (ESIneg): m/z = 520 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.194 (15.73), 1.212 (16.00), 2.327 (0.46), 2.366 (0.64), 2.563 (8.94), 2.574 (4.73), 2.592 (1.82), 2.602 (1.00), 2.670 (0.46), 2.710 (0.64), 3.361 (1.43), 3.379 (4.41), 3.396 (4.24), 3.413 (1.19), 3.675 (8.01), 3.686 (14.00), 3.697 (7.75), 7.258 (3.16), 7.360 (3.02), 7.366 (2.99), 7.382 (4.11), 7.388 (4.16), 7.441 (6.43), 7.482 (6.02), 7.503 (4.16), 7.557 (2.94), 7.569 (3.12), 7.577 (3.10), 7.588 (3.12), 7.625 (3.02), 7.983 (3.56), 7.987 (3.65), 8.004 (3.97), 8.008 (4.16), 8.115 (7.33), 8.118 (6.85), 8.279 (3.63), 8.288 (7.41), 8.299 (3.53), 8.309 (6.14), 8.401 (13.25), 8.451 (6.18), 8.457 (6.13), 8.668 (3.90), 8.671 (3.83), 8.680 (3.87), 9.077 (5.82), 9.082 (5.75), 10.105 (7.02).
Example 124
N-{2-(difluoromethoxy)-5-[4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]phenyl}-2-(morpholin-4- yl)propanamide (enantiomer 2)
Figure imgf000236_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (enantiomer 2) (150 mg, 287 μιηοΐ), pyridin-3-ylboronic acid (52.8 mg, 430 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (11.7 mg, 14.3 μιηοΐ) and potassium carbonate (119 mg, 860 μιηοΐ) in N,N-dimethylformamide (250 μΐ), water (1.1 ml) and 1,2-dimethoxyethane (1.6 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by a preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid) to afford 105 mg (97 % purity, 68 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.35 min; MS (ESIneg): m/z = 520 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.194 (15.73), 1.212 (16.00), 2.366 (0.43), 2.562 (8.58), 2.574 (4.60), 2.592 (1.81), 2.603 (1.03), 2.670 (0.45), 2.710 (0.49), 3.361 (1.38), 3.379 (4.39), 3.396 (4.28), 3.413 (1.23), 3.675 (7.62), 3.686 (13.51), 3.697 (7.54), 7.258 (3.21), 7.360 (3.07), 7.367 (3.02), 7.382 (4.17), 7.388 (4.22), 7.442 (6.65), 7.482 (6.01), 7.503 (4.13), 7.557 (2.73), 7.569 (2.92), 7.577 (2.94), 7.588 (2.96), 7.625 (3.09), 7.983 (3.57), 7.987 (3.57), 8.004 (3.99), 8.008 (4.13), 8.114 (7.38), 8.118 (6.73), 8.279 (3.41), 8.288 (7.43), 8.295 (2.63), 8.299 (3.36), 8.309 (6.24), 8.401 (13.78), 8.451 (6.34), 8.457 (6.23), 8.669 (3.61), 8.681 (3.60), 9.077 (5.01), 9.082 (4.91), 10.105 (6.84).
Example 125
N-{5-[7-(5-cyanopyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(difluoromethoxy)phenyl} -l-(4- methylpiperazin-1 -yl)cyclopropane-l -carboxamide
Figure imgf000237_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (200 mg, 365 μιηοΐ), (5-cyanopyridin-3-yl)boronic acid (80.9 mg, 547 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (14.9 mg, 18.2 μιηοΐ) and potassium carbonate (151 mg, 1.09 mmol) in N,N- dimethylformamide (320 μΐ), water (1.4 ml) and 1,2-dimethoxyethane (2.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 100:0 to 85: 15 followed by a second chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to ethyl acetate/methanol 80:20 to afford 121 mg (99 % purity, 57 % yield) of the title compound.
LC-MS (Method 4): Rt = 0.88 min; MS (ESIpos): m/z = 572 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.51), 0.008 (2.37), 1.092 (1.36), 1.105 (3.66), 1.112 (4.23), 1.122 (2.08), 1.214 (2.01), 1.223 (4.30), 1.230 (3.52), 1.243 (1.51), 1.907 (0.43), 2.207 (16.00), 2.327 (1.29), 2.366 (1.65), 2.457 (5.17), 2.523 (6.53), 2.669 (1.22), 2.710 (1.43), 7.319 (1.87), 7.339 (1.94), 7.345 (2.01), 7.360 (2.44), 7.367 (2.51), 7.498 (3.66), 7.503 (4.74), 7.519 (2.58), 7.687 (1.87), 8.053 (2.01), 8.058 (2.08), 8.074 (2.30), 8.079 (2.58), 8.239 (4.09), 8.243 (4.09), 8.299 (4.02), 8.319 (3.37), 8.412 (8.39), 8.572 (3.95), 8.579 (4.09), 8.875 (2.44), 8.880 (4.38), 8.885 (2.73), 9.109 (3.87), 9.113 (3.87), 9.372 (4.09), 9.378 (4.09), 10.711 (3.87).
Example 126
N-[2-(difluoromethoxy)-5-(4-oxo-7-phenylquinazolin-3(4H)-yl)phenyl]-l-(4-methylpiperazin-l- yl)cyclopropane-l -carboxamide
Figure imgf000238_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (200 mg, 365 μιηοΐ), phenylboronic acid (66.7 mg, 547 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (14.9 mg, 18.2 μιηοΐ) and potassium carbonate (151 mg, 1.09 mmol) in N,N-dimethylformamide (320 μΐ), water (1.4 ml) and 1 ,2-dimethoxyethane (2.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to ethyl acetate/methanol 85:15 followed by a second chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to ethyl acetate/methanol 80:20 to afford 33.7 mg (95 % purity, 16 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.05 min; MS (ESIpos): m/z = 546 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.150 (0.59), 1.094 (1.87), 1.106 (4.71), 1.114 (5.40), 1.123 (2.65), 1.222 (5.50), 2.209 (16.00), 2.328 (1.87), 2.366 (1.96), 2.458 (6.48), 2.670 (1.87), 2.710 (1.67), 7.316 (2.36), 7.332 (2.55), 7.338 (2.45), 7.353 (2.94), 7.360 (2.94), 7.461 (1.08), 7.480 (3.63), 7.494 (5.79), 7.500 (6.97), 7.515 (3.14), 7.534 (4.12), 7.553 (6.09), 7.571 (2.65), 7.684 (2.16), 7.851 (5.89), 7.869 (5.50), 7.921 (2.45), 7.925 (2.75), 7.941 (2.75), 7.946 (3.14), 8.008 (5.30), 8.011 (4.91), 8.254 (4.71), 8.275 (4.22), 8.373 (10.40), 8.562 (4.42), 8.568 (4.52), 10.708 (4.12). Example 127
N- {2-(difluoromethoxy)-5-[7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]phenyl} -1 -(4- methylpiperazin-1 -yl)cyclopropane-l -carboxamide
Figure imgf000239_0001
A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (200 mg, 365 μηιοΐ), (2-fluorophenyl)boronic acid (76.5 mg, 547 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (14.9 mg, 18.2 μηιοΐ) and potassium carbonate (151 mg, 1.09 mmol) in N,N- dimethylformamide (320 μΐ), water (1.4 ml) and 1,2-dimethoxyethane (2.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to ethyl acetate/methanol 85: 15 followed by a second chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 to ethyl acetate/methanol 80:20 to afford 96.0 mg (95 % purity, 44 % yield) of the title compound.
LC-MS (Method 4): Rt = 1.05 min; MS (ESIpos): m z = 564 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.098 (3.45), 1.110 (8.30), 1.118 (9.70), 1.127 (4.72), 1.170 (1.09), 1.213 (4.85), 1.222 (10.09), 1.229 (8.12), 1.242 (3.35), 2.229 (13.56), 2.328 (0.96), 2.366 (1.32), 2.466 (10.32), 2.670 (0.91), 2.710 (0.99), 7.313 (4.15), 7.333 (4.12), 7.339 (4.18), 7.355 (5.06), 7.361 (5.34), 7.379 (3.29), 7.386 (6.41), 7.404 (6.74), 7.425 (3.50), 7.496 (14.18), 7.508 (2.72), 7.517 (7.44), 7.538 (2.57), 7.556 (1.06), 7.680 (6.04), 7.701 (4.54), 7.705 (4.28), 7.720 (2.44), 7.779 (4.80), 7.800 (4.88), 7.899 (8.38), 7.971 (0.44), 8.092 (0.52), 8.114 (0.52), 8.268 (7.86), 8.288 (7.21), 8.379 (16.00), 8.538 (0.57), 8.559 (6.04), 8.565 (5.99), 10.690 (4.51).
Example 128
N-{5-[8-fluoro-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1)
Figure imgf000240_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1) (100 mg, 174 μιηοΐ), (2-fluorophenyl)boronic acid (36.6 mg, 262 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (660 μΐ) and 1, 2 -dimethoxy ethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0:100 to afford 85.0 mg (99 % purity, 83 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.74 min; MS (ESIpos): m/z = 589 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.41), -0.007 (3.25), 0.008 (3.75), 1.194 (15.69), 1.212 (16.00), 1.841 (1.08), 1.857 (3.15), 1.871 (4.50), 1.885 (3.54), 1.900 (1.29), 2.328 (0.64), 2.367 (0.83), 2.670 (0.73), 2.710 (1.82), 2.743 (9.31), 2.756 (8.21), 2.766 (2.72), 2.789 (0.81), 3.655 (4.77), 3.667 (9.49), 3.678 (5.12), 3.685 (5.10), 3.702 (4.23), 3.719 (1.31), 3.736 (5.84), 3.751 (11.21), 3.766 (5.76), 5.754 (0.89), 7.390 (2.26), 7.400 (2.11), 7.408 (5.33), 7.426 (5.14), 7.434 (4.04), 7.441 (4.10), 7.447 (2.88), 7.456 (4.08), 7.462 (4.14), 7.566 (1.68), 7.575 (2.88), 7.579 (2.84), 7.584 (2.78), 7.596 (4.95), 7.615 (2.82), 7.639 (2.49), 7.659 (3.13), 7.676 (3.11), 7.683 (3.30), 7.686 (3.40), 7.705 (2.74), 7.708 (2.65), 8.085 (5.24), 8.105 (4.73), 8.475 (12.25), 8.485 (6.71), 8.491 (6.63), 10.102 (6.90).
Example 129
N-[5-(8-fluoro-4-oxo-7-phenylquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4-oxazepan-4- yl)propanamide (enantiomer 1)
Figure imgf000240_0002
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1) (100 mg, 174 μιηοΐ), phenylboronic acid (31.9 mg, 262 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (660 μΐ) and 1, 2 -dimethoxy ethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 54.0 mg (99 % purity, 54 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.75 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.45), -0.008 (3.83), 0.008 (4.75), 0.146 (0.47), 1.194 (15.78), 1.211 (16.00), 1.841 (1.02), 1.856 (2.91), 1.870 (4.16), 1.885 (3.33), 1.900 (1.24), 2.328 (0.60), 2.367 (0.80), 2.524 (2.89), 2.670 (0.67), 2.710 (1.72), 2.722 (3.31), 2.743 (8.78), 2.755 (7.79), 2.766 (2.61), 2.788 (0.85), 3.655 (4.55), 3.666 (8.96), 3.678 (4.93), 3.684 (5.18), 3.702 (4.38), 3.719 (1.32), 3.735 (6.07), 3.751 (11.70), 3.765 (6.00), 7.434 (3.76), 7.440 (3.76), 7.456 (4.21), 7.462 (4.40), 7.490 (1.29), 7.502 (1.02), 7.508 (4.60), 7.514 (1.52), 7.523 (2.21), 7.526 (4.08), 7.530 (2.36), 7.554 (5.70), 7.569 (4.40), 7.573 (9.11), 7.586 (1.69), 7.591 (4.16), 7.594 (2.81), 7.681 (10.23), 7.684 (9.60), 7.702 (8.09), 7.718 (3.19), 7.736 (3.48), 7.739 (3.76), 7.757 (3.31), 8.066 (5.10), 8.087 (4.48), 8.471 (13.34), 8.480 (6.89), 8.486 (6.74), 10.102 (6.42).
Example 130
N-{5-[8-fluoro-7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2- (morpholin-4-yl)propanamide (enantiomer 1)
Figure imgf000241_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 1) (100 mg, 179 μιηοΐ), (5-fluoropyridin-3-yl)boronic acid (37.8 mg, 268 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (7.30 mg, 8.94 μιηοΐ) and potassium carbonate (74.1 mg, 536 μιηοΐ) in N,N- dimethylformamide (160 μΐ), water (680 μΐ) and 1,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 to afford 86.0 mg (99 % purity, 84 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.72 min; MS (ESIpos): m/z = 576 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.42), -0.008 (3.60), 0.008 (4.05), 0.146 (0.45), 1.175 (0.81), 1.200 (15.72), 1.217 (16.00), 1.988 (1.23), 2.323 (0.64), 2.327 (0.92), 2.332 (0.64), 2.366 (0.67), 2.518 (5.70), 2.523 (4.83), 2.568 (7.29), 2.580 (4.13), 2.598 (1.65), 2.609 (1.01), 2.665 (0.73), 2.670 (0.98), 2.674 (0.75), 2.710 (0.78), 3.387 (1.28), 3.404 (4.50), 3.422 (4.41), 3.439 (1.23), 3.648 (6.00), 3.659 (10.53), 3.670 (6.00), 7.449 (3.80), 7.456 (3.77), 7.471 (4.27), 7.477 (4.41), 7.689 (3.10), 7.692 (3.21), 7.711 (2.74), 7.714 (2.54), 7.826 (2.74), 7.843 (3.13), 7.847 (3.41), 7.864 (3.10), 8.100 (4.77), 8.121 (4.02), 8.144 (2.35), 8.169 (2.35), 8.449 (6.25), 8.455 (6.25), 8.501 (12.31), 8.730 (5.84), 8.737 (5.72), 8.791 (4.52), 8.795 (4.61), 10.106 (6.42).
Example 131
N-{5-[8-fluoro-7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2- (morpholin-4-yl)propanamide (enantiomer 2)
Figure imgf000242_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 2) (100 mg, 179 μιηοΐ), (5-fluoropyridin-3-yl)boronic acid (37.8 mg, 268 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (7.30 mg, 8.94 μιηοΐ) and potassium carbonate (74.1 mg, 536 μιηοΐ) in N,N- dimethylformamide (160 μΐ), water (680 μΐ) and 1,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 to afford 45.0 mg (99 % purity, 44 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.72 min; MS (ESIpos): m/z = 576 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.05), 0.008 (2.05), 1.200 (15.74), 1.217 (16.00), 2.328 (0.90), 2.366 (1.54), 2.568 (8.19), 2.580 (4.48), 2.598 (1.79), 2.609 (1.02), 2.670 (1.02), 2.710 (1.54), 3.265 (0.64), 3.387 (1.66), 3.405 (4.61), 3.422 (4.61), 3.439 (1.28), 3.648 (6.53), 3.659 (11.39), 3.670 (6.53), 7.449 (3.46), 7.456 (3.46), 7.471 (3.97), 7.478 (4.10), 7.689 (3.07), 7.693 (3.20), 7.711 (2.69), 7.715 (2.56), 7.827 (2.56), 7.844 (3.07), 7.848 (3.46), 7.865 (3.07), 8.100 (5.12), 8.121 (4.22), 8.144 (2.43), 8.169 (2.43), 8.448 (6.02), 8.455 (6.14), 8.501 (12.16), 8.730 (5.89), 8.737 (5.89), 8.792 (4.74), 8.795 (4.99), 10.108 (6.66).
Example 132
N- { 5 - [ 8 -fluoro -4 -oxo -7 -(pyridin-3 -yl)quinazo
4-yl)propanamide (enantiomer 1)
Figure imgf000243_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 1) (100 mg, 179 μιηοΐ), pyridin-3 -ylboronic acid (33.0 mg, 268 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane -complex (7.30 mg, 8.94 μιηοΐ) and potassium carbonate (74.1 mg, 536 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (680 μΐ) and 1 ,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 31.0 mg (99 % purity, 31 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.52 min; MS (ESIneg): m/z = 556 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.49), -0.008 (4.10), 0.008 (4.58), 0.146 (0.49), 1.201 (15.80), 1.218 (16.00), 2.328 (0.59), 2.367 (0.95), 2.524 (4.35), 2.598 (1.61), 2.609 (0.97), 2.670 (0.67), 2.710 (0.95), 3.387 (1.31), 3.405 (4.53), 3.422 (4.40), 3.440 (1.15), 3.648 (6.22), 3.659 (10.83), 3.670 (6.17), 7.449 (3.79), 7.455 (3.76), 7.471 (4.25), 7.477 (4.45), 7.593 (2.56), 7.605 (2.71), 7.613 (2.76), 7.625 (2.79), 7.688 (3.25), 7.692 (3.33), 7.710 (2.87), 7.714 (2.64), 7.788 (2.74), 7.805 (3.30), 7.809 (3.58), 7.826 (3.12), 8.096 (5.04), 8.116 (4.48), 8.129 (2.59), 8.148 (2.36), 8.446 (6.68), 8.453 (6.68), 8.490 (12.98), 8.695 (3.56), 8.699 (3.61), 8.707 (3.61), 8.711 (3.48), 8.896 (4.71), 10.107 (6.53). Example 133
N- { 5 - [ 8 -fluoro -4 -oxo -7 -(pyridin-3 -yl)quina
4-yl)propanamide (enantiomer 2)
Figure imgf000244_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 2) (100 mg, 179 μιηοΐ), pyridin-3 -ylboronic acid (33.0 mg, 268 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane -complex (7.30 mg, 8.94 μιηοΐ) and potassium carbonate (74.1 mg, 536 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (680 μΐ) and 1 ,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 to afford 47.0 mg (99 % purity, 47 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.52 min; MS (ESIneg): m/z = 556 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.78), 0.008 (2.97), 1.201 (15.75), 1.218 (16.00), 2.328 (0.40), 2.366 (0.63), 2.519 (3.14), 2.524 (3.20), 2.569 (7.13), 2.580 (4.07), 2.598 (1.56), 2.609 (0.89), 2.710 (0.61), 3.387 (1.27), 3.405 (4.45), 3.422 (4.34), 3.440 (1.16), 3.648 (6.18), 3.659 (10.71), 3.670 (6.07), 7.449 (3.77), 7.455 (3.65), 7.471 (4.20), 7.477 (4.34), 7.593 (2.55), 7.605 (2.66), 7.613 (2.72), 7.625 (2.74), 7.688 (3.10), 7.692 (3.20), 7.710 (2.74), 7.714 (2.51), 7.787 (2.74), 7.805 (3.23), 7.808 (3.48), 7.825 (3.10), 8.095 (4.76), 8.116 (4.24), 8.129 (2.49), 8.147 (2.26), 8.447 (6.09), 8.453 (6.03), 8.490 (12.10), 8.695 (3.14), 8.699 (3.18), 8.707 (3.16), 8.711 (3.02), 8.896 (4.19), 10.107 (6.47).
Example 134
N-{5-[8-fluoro-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2- (morpholin-4-yl)propanamide (enantiomer 1)
Figure imgf000245_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 1) (100 mg, 179 μηιοΐ), (2-fluorophenyl)boronic acid (37.5 mg, 268 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (7.30 mg, 8.94 μηιοΐ) and potassium carbonate (74.1 mg, 536 μηιοΐ) in N,N-dimethylformamide (160 μΐ), water (680 μΐ) and 1 ,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 to afford 99.0 mg (99 % purity, 96 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.04 min; MS (ESIpos): m/z = 575 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.205 (15.92), 1.217 (16.00), 2.422 (1.07), 2.466 (0.78), 2.564 (4.04), 2.572 (5.36), 2.579 (4.12), 2.591 (2.10), 2.598 (1.36), 2.652 (1.07), 3.263 (1.98), 3.338 (0.49), 3.392 (1.36), 3.404 (4.25), 3.416 (4.21), 3.427 (1.28), 3.659 (9.40), 5.747 (5.86), 7.394 (2.35), 7.406 (5.65), 7.418 (6.85), 7.434 (2.52), 7.448 (3.26), 7.452 (3.26), 7.462 (3.63), 7.467 (3.67), 7.571 (1.65), 7.580 (3.13), 7.591 (5.53), 7.603 (2.97), 7.642 (2.47), 7.654 (3.22), 7.666 (2.60), 7.686 (3.51), 7.700 (3.09), 8.086 (5.69), 8.099 (5.32), 8.445 (5.98), 8.449 (6.10), 8.465 (12.70), 10.094 (6.72).
Example 135
N-{5-[8-fluoro-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2- (morpholin-4-yl)propanamide (enantiomer 2)
Figure imgf000245_0002
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 2) (100 mg, 179 μηιοΐ), (2-fluorophenyl)boronic acid (37.5 mg, 268 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (7.30 mg, 8.94 μηιοΐ) and potassium carbonate (74.1 mg, 536 μηιοΐ) in N,N-dimethylformamide (160 μΐ), water (680 μΐ) and 1 ,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0:100 to afford 78.0 mg (99 % purity, 76 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.03 min; MS (ESIpos): m/z = 575 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.51), -0.008 (3.97), 0.008 (4.36), 0.146 (0.46), 1.175 (0.68), 1.201 (15.71), 1.219 (16.00), 1.398 (0.87), 1.988 (1.02), 2.073 (0.90), 2.327 (0.80), 2.366 (0.87), 2.523 (4.60), 2.569 (7.26), 2.580 (4.19), 2.599 (1.65), 2.609 (0.97), 2.670 (0.85), 2.710 (0.92), 3.387 (1.28), 3.404 (4.50), 3.422 (4.41), 3.439 (1.23), 3.648 (6.08), 3.659 (10.82), 3.670 (6.17), 7.390 (2.25), 7.400 (2.06), 7.408 (5.06), 7.421 (3.90), 7.426 (5.06), 7.445 (6.15), 7.452 (4.09), 7.467 (4.24), 7.474 (4.41), 7.565 (1.77), 7.575 (2.74), 7.579 (2.69), 7.583 (2.66), 7.595 (4.65), 7.609 (1.67), 7.614 (2.78), 7.638 (2.52), 7.654 (2.81), 7.658 (3.00), 7.675 (2.81), 7.687 (3.29), 7.690 (3.36), 7.709 (2.83), 7.712 (2.61), 8.084 (5.06), 8.104 (4.57), 8.446 (6.61), 8.452 (6.61), 8.471 (12.85), 10.105 (6.61). Example 136
N-[5-(8-fluoro-4-oxo-7-phenylquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(morpholin-4- yl)propanamide (enantiomer 1)
Figure imgf000246_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 1) (100 mg, 179 μηιοΐ), phenylboronic acid (32.7 mg, 268 μηιοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane -complex (7.30 mg, 8.94 μηιοΐ) and potassium carbonate (74.1 mg, 536 μηιοΐ) in N,N-dimethylformamide (160 μΐ), water (680 μΐ) and 1,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 50.0 mg (99 % purity, 50 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.05 min; MS (ESIpos): m/z = 557 [M+H] i+ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.68), -0.008 (5.31), 0.008 (6.13), 0.146 (0.59), 1.201 (15.75), 1.218 (16.00), 2.328 (1.10), 2.366 (1.19), 2.598 (1.67), 2.670 (1.10), 2.710 (1.16), 3.386 (1.30), 3.404 (4.41), 3.421 (4.38), 3.439 (1.24), 3.659 (11.76), 7.445 (3.56), 7.452 (3.59), 7.467 (4.13), 7.473 (4.30), 7.490 (1.36), 7.508 (4.44), 7.526 (3.73), 7.554 (5.68), 7.573 (8.76), 7.591 (3.84), 7.684 (9.75), 7.702 (6.56), 7.718 (3.25), 7.738 (3.76), 7.756 (3.08), 8.065 (5.40), 8.086 (4.75), 8.440 (6.90), 8.446 (6.87), 8.467 (13.17), 10.105 (6.93).
Example 137
N-[5-(8-fluoro-4-oxo-7-phenylquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(mo^holin-4- yl)propanamide (enantiomer 2)
Figure imgf000247_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 2) (100 mg, 179 μιηοΐ), phenylboronic acid (32.7 mg, 268 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane -complex (7.30 mg, 8.94 μιηοΐ) and potassium carbonate (74.1 mg, 536 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (680 μΐ) and 1,2-dimethoxyethane (1.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0:100 to afford 70.0 mg (99 % purity, 70 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.05 min; MS (ESIpos): m/z = 557 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.16), 0.008 (1.28), 1.201 (15.77), 1.218 (16.00), 2.073 (0.52), 2.328 (0.52), 2.367 (0.70), 2.569 (7.45), 2.580 (4.31), 2.598 (1.63), 2.609 (0.93), 2.670 (0.52), 2.710 (0.76), 3.386 (1.40), 3.404 (4.60), 3.421 (4.36), 3.438 (1.22), 3.648 (6.28), 3.659 (11.00), 3.670 (6.34), 7.445 (3.67), 7.452 (3.67), 7.467 (4.25), 7.474 (4.42), 7.490 (1.28), 7.502 (0.99), 7.508 (4.36), 7.514 (1.40), 7.523 (2.27), 7.526 (3.84), 7.530 (2.21), 7.554 (5.41), 7.569 (4.36), 7.573 (8.61), 7.586 (1.69), 7.591 (3.96), 7.681 (8.26), 7.684 (8.90), 7.702 (6.28), 7.706 (5.06), 7.711 (3.26), 7.718 (3.20), 7.735 (3.43), 7.739 (3.55), 7.756 (3.08), 8.064 (4.77), 8.085 (4.25), 8.440 (6.17), 8.446 (6.17), 8.467 (12.28), 10.106 (6.46). Example 138
N-{5-[8-fluoro-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -l - (morpholin-4-yl)cyclopropane- 1 -carboxamide
Figure imgf000248_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l -carboxamide (120 mg, 210 μηιοΐ), (2-fluorophenyl)boronic acid (44.1 mg, 315 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane-complex (8.58 mg, 10.5 μηιοΐ) and potassium carbonate (87.1 mg, 630 μηιοΐ) in N,N-dimethylformamide (190 μΐ), water (800 μΐ) and 1 ,2-dimethoxyethane (1.2 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0:100 to afford 104 mg (99 % purity, 84 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.31 min; MS (ESIpos): m/z = 587 [M+H]+
Ή-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.128 (3.24), 1.136 (9.94), 1.141 (10.35), 1.149 (4.47), 1.176 (0.41), 1.249 (0.59), 1.276 (4.10), 1.283 (10.44), 1.289 (9.25), 1.297 (3.56), 2.384 (0.55), 2.423 (1.14), 2.473 (12.85), 2.570 (1.05), 2.612 (0.55), 2.652 (1.00), 3.263 (2.32), 3.328 (2.19), 3.708 (13.04), 6.481 (0.68), 7.392 (2.96), 7.404 (6.93), 7.416 (8.75), 7.429 (5.24), 7.433 (7.43), 7.443 (4.83), 7.447 (4.97), 7.575 (3.37), 7.578 (3.56), 7.588 (6.20), 7.601 (3.15), 7.638 (2.92), 7.651 (3.87), 7.662 (3.19), 7.714 (4.19), 7.727 (3.74), 8.080 (7.02), 8.093 (6.52), 8.140 (0.50), 8.458 (16.00), 8.595 (8.48), 8.599 (8.52), 10.622 (9.07).
Example 139
N-[5-(8-fluoro-4-oxo-7-phenylquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide
Figure imgf000249_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (120 mg, 210 μιηοΐ), phenylboronic acid (38.4 mg, 315 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane -complex (8.58 mg, 10.5 μιηοΐ) and potassium carbonate (87.1 mg, 630 μιηοΐ) in N,N-dimethylformamide (190 μΐ), water (800 μΐ) and 1,2-dimethoxyethane (1.2 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 87.0 mg (99 % purity, 73 % yield) of the title compound.
LC-MS (Method 6): Rt = 2.34 min; MS (ESIpos): m/z = 569 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.41), -0.008 (3.97), 0.008 (3.62), 0.146 (0.41), 1.120 (3.59), 1.132 (10.10), 1.139 (11.10), 1.150 (5.08), 1.192 (0.49), 1.233 (1.23), 1.274 (4.77), 1.284 (10.97), 1.292 (9.28), 1.304 (3.64), 2.073 (0.51), 2.328 (0.95), 2.366 (0.90), 2.472 (15.87), 2.483 (13.62), 2.670 (0.92), 2.710 (0.79), 3.707 (15.46), 7.425 (4.95), 7.432 (4.90), 7.447 (5.64), 7.454 (5.72), 7.488 (1.64), 7.506 (5.92), 7.524 (5.10), 7.551 (7.85), 7.570 (12.21), 7.588 (5.38), 7.678 (10.72), 7.698 (8.00), 7.713 (8.23), 7.734 (8.85), 7.751 (4.13), 8.057 (6.90), 8.078 (6.13), 8.459 (16.00), 8.590 (10.36), 8.597 (10.31), 10.631 (10.18).
Example 140
N-{5-[8-fluoro-4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1)
Figure imgf000249_0002
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1) (100 mg, 174 μιηοΐ), pyridin-3-ylboronic acid (32.2 mg, 262 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (660 μΐ) and 1, 2 -dimethoxy ethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture filtered through celite, rinsing with a mixture of dichloromethane/methanol 4: 1 and the filtrate was evaporated. The residue was purified by preparative RP-HPLC with acetonitrile/water (0.1% formic acid) to afford 52.0 mg (99 % purity, 52 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.26 min; MS (ESIneg): m/z = 570 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.92), 0.008 (1.01), 1.194 (14.06), 1.21 1 (14.29), 1.841 (0.92), 1.856 (2.58), 1.870 (3.69), 1.885 (2.90), 1.900 (1.11), 2.328 (0.41), 2.367 (0.78), 2.523 (1.84), 2.525 (1.75), 2.558 (1.06), 2.560 (0.88), 2.563 (0.69), 2.565 (0.55), 2.568 (0.51), 2.671 (0.51), 2.710 (1.61), 2.722 (2.90), 2.743 (7.70), 2.756 (6.73), 2.766 (2.17), 2.789 (0.69), 3.655 (4.15), 3.667 (7.88), 3.678 (4.29), 3.685 (4.43), 3.703 (3.87), 3.720 (1.15), 3.736 (5.26), 3.751 (10.01), 3.766 (5.12), 7.437 (3.32), 7.444 (3.27), 7.459 (3.73), 7.466 (3.87), 7.593 (2.40), 7.605 (2.49), 7.613 (2.54), 7.625 (2.63), 7.684 (2.77), 7.688 (2.86), 7.706 (2.40), 7.710 (2.26), 7.788 (2.40), 7.806 (2.81), 7.809 (3.09), 7.826 (2.77), 8.097 (4.33), 8.118 (3.87), 8.129 (2.26), 8.148 (2.03), 8.486 (5.95), 8.493 (16.00), 8.695 (3.23), 8.699 (3.32), 8.707 (3.27), 8.711 (3.18), 8.896 (4.01), 10.104 (5.44).
Example 141
N-{5-[8-fluoro-4-oxo-7-(pyridin-3-yl)quinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2)
Figure imgf000250_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2) (100 mg, 174 μιηοΐ), pyridin-3-ylboronic acid (32.2 mg, 262 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (660 μΐ) and 1,2 -dimethoxy ethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture filtered through celite, rinsing with a mixture of dichloromethane/methanol 4:1 and the filtrate was evaporated. The residue was purified by preparative RP-HPLC with acetonitrile/water (0.1% formic acid) to afford 33.0 mg (99 % purity, 33 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.26 min; MS (ESIneg): m/z = 570 [M-H]"
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.96), 0.008 (1.00), 1.194 (13.25), 1.211 (13.50), 1.841 (0.88), 1.856 (2.46), 1.870 (3.42), 1.885 (2.75), 1.900 (1.00), 2.328 (0.46), 2.367 (0.83), 2.524 (1.96), 2.671 (0.50), 2.710 (1.63), 2.743 (7.12), 2.756 (6.29), 2.766 (2.04), 2.789 (0.67), 3.655 (3.83), 3.667 (7.42), 3.678 (4.00), 3.685 (4.17), 3.703 (3.67), 3.720 (1.08), 3.736 (4.96), 3.751 (9.54), 3.766 (4.83), 7.437 (3.17), 7.444 (3.17), 7.459 (3.58), 7.466 (3.71), 7.593 (2.25), 7.605 (2.33), 7.613 (2.37), 7.625 (2.46), 7.684 (2.63), 7.688 (2.75), 7.706 (2.29), 7.710 (2.17), 7.788 (2.29), 7.806 (2.67), 7.809 (2.92), 7.826 (2.58), 8.096 (4.21), 8.117 (3.75), 8.129 (2.12), 8.147 (1.92), 8.486 (6.00), 8.493 (16.00), 8.695 (3.33), 8.699 (3.37), 8.707 (3.33), 8.711 (3.25), 8.896 (4.04), 10.104 (5.17).
Example 142
N-{5-[8-fluoro-7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1)
Figure imgf000251_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1) (100 mg, 174 μιηοΐ), (5-fluoropyridin-3-yl)boronic acid (36.9 mg, 262 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N- dimethylformamide (160 μΐ), water (660 μΐ) and 1,2-dimethoxyethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture filtered through celite, rinsing with a mixture of dichloromethane/methanol 4: 1 and the filtrate was evaporated. The residue was purified by preparative RP-HPLC with acetonitrile/water (0.1 % formic acid) to afford 42.0 mg (96 % purity, 38 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.45 min; MS (ESIpos): m/z = 590 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (1.96), 1.193 (15.66), 1.211 (16.00), 1.841 (1.22), 1.856 (2.97), 1.870 (4.12), 1.885 (3.24), 1.900 (1.28), 2.329 (0.81), 2.367 (1.28), 2.670 (1.01), 2.710 (2.50), 2.743 (8.64), 2.756 (7.56), 3.655 (4.79), 3.666 (8.78), 3.678 (4.86), 3.685 (5.06), 3.703 (4.32), 3.720 (1.42), 3.735 (5.94), 3.751 (11.27), 3.765 (5.81), 6.524 (0.47), 7.438 (3.65), 7.445 (3.65), 7.460 (4.05), 7.467 (4.25), 7.685 (3.04), 7.689 (3.24), 7.707 (2.77), 7.711 (2.57), 7.827 (2.70), 7.845 (3.11), 7.848 (3.38), 7.865 (3.11), 8.101 (5.00), 8.122 (4.19), 8.145 (2.50), 8.170 (2.43), 8.488 (6.62), 8.495 (6.75), 8.504 (12.89), 8.631 (0.41), 8.731 (6.35), 8.737 (6.35), 8.792 (4.86), 8.796 (5.00), 10.104 (6.01).
Example 143
N-{5-[8-fluoro-7-(5-fluoropyridin-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethox
oxazepan-4-yl)propanamide (enantiomer 2)
Figure imgf000252_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2) (100 mg, 174 μηιοΐ), (5-fluoropyridin-3-yl)boronic acid (36.9 mg, 262 μηιοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]-dichloropalladium-dichloromethane- complex (7.12 mg, 8.72 μηιοΐ) and potassium carbonate (72.3 mg, 523 μηιοΐ) in N,N- dimethylformamide (160 μΐ), water (660 μΐ) and 1,2-dimethoxyethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture filtered through celite, rinsing with a mixture of dichloromethane/methanol 4: 1 and the filtrate was evaporated. The residue was purified by preparative RP-HPLC with acetonitrile/water (0.1% formic acid) to afford 40.0 mg (99 % purity, 39 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.44 min; MS (ESIpos): m/z = 590 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.63), 0.008 (3.00), 1.193 (15.87), 1.210 (16.00), 1.841 (1.00), 1.855 (2.88), 1.870 (4.00), 1.884 (3.25), 1.900 (1.25), 2.328 (1.25), 2.367 (2.12), 2.524 (5.12), 2.670 (1.37), 2.710 (3.00), 2.743 (8.37), 2.755 (7.37), 2.789 (0.88), 3.655 (4.50), 3.666 (8.63), 3.677 (4.75), 3.685 (5.00), 3.703 (4.37), 3.720 (1.37), 3.735 (6.00), 3.750 (11.37), 3.765 (5.75), 7.438 (3.75), 7.445 (3.75), 7.460 (4.25), 7.466 (4.37), 7.685 (3.12), 7.689 (3.12), 7.707 (2.88), 7.711 (2.50), 7.828 (2.75), 7.845 (3.12), 7.849 (3.37), 7.865 (3.25), 8.102 (5.00), 8.122 (4.12), 8.145 (2.37), 8.170 (2.25), 8.488 (6.63), 8.494 (6.75), 8.504 (12.88), 8.730 (6.12), 8.737 (6.00), 8.792 (4.75), 8.796 (4.75), 10.104 (6.12). Example 144
N-[5-(8-fluoro-4-oxo-7-phenylquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4-oxazepan-4- yl)propanamide (enantiomer 2)
Figure imgf000253_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2) (100 mg, 174 μιηοΐ), phenylboronic acid (31.9 mg, 262 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (660 μΐ) and 1, 2 -dimethoxy ethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture filtered through celite, rinsing with a mixture of dichloromethane/methanol 4:1 and the filtrate was evaporated. The residue was purified by preparative RP-HPLC with acetonitrile/water (0.1% formic acid) to afford 42.0 mg (99 % purity, 42 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.75 min; MS (ESIpos): m/z = 571 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.24), 0.008 (1.45), 1.194 (15.64), 1.211 (16.00), 1.841 (1.04), 1.856 (3.00), 1.870 (4.19), 1.885 (3.37), 1.900 (1.24), 2.328 (0.62), 2.367 (0.83), 2.670 (0.62), 2.710 (1.76), 2.743 (8.80), 2.756 (7.82), 2.765 (2.59), 2.789 (0.83), 3.655 (4.61), 3.666 (9.11), 3.678 (4.97), 3.684 (5.13), 3.702 (4.35), 3.719 (1.29), 3.736 (5.90), 3.751 (11.29), 3.765 (5.75), 7.434 (3.73), 7.440 (3.73), 7.456 (4.14), 7.462 (4.40), 7.490 (1.24), 7.508 (4.35), 7.514 (1.45), 7.527 (3.78), 7.554 (5.64), 7.573 (8.65), 7.591 (3.88), 7.681 (10.15), 7.702 (7.97), 7.719 (3.00), 7.739 (3.62), 7.757 (3.11), 8.066 (5.13), 8.087 (4.50), 8.471 (13.10), 8.480 (7.04), 8.486 (6.89), 10.103 (6.32).
Example 145
N-{5-[8-fluoro-7-(2-fluorophenyl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl} -2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2)
Figure imgf000254_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2) (100 mg, 174 μιηοΐ), (2-fluorophenyl)boronic acid (36.6 mg, 262 μιηοΐ), [1,1 -bis-(diphenylphosphino)-ferrocen] -dichloropalladium-dichloromethane -complex (7.12 mg, 8.72 μιηοΐ) and potassium carbonate (72.3 mg, 523 μιηοΐ) in N,N-dimethylformamide (160 μΐ), water (660 μΐ) and 1, 2 -dimethoxy ethane (980 μΐ) was degassed by passing argon through it for 5 min and then the mixture was heated at 80°C for 2 h. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 57.0 mg (99 % purity, 56 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.74 min; MS (ESIpos): m/z = 589 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.32), 0.008 (1.48), 1.194 (15.74), 1.212 (16.00), 1.841 (1.00), 1.856 (2.90), 1.871 (4.01), 1.885 (3.22), 1.900 (1.21), 2.328 (0.63), 2.367 (0.90), 2.524 (2.48), 2.670 (0.69), 2.711 (1.80), 2.743 (8.50), 2.756 (7.60), 2.766 (2.43), 2.789 (0.79), 3.655 (4.49), 3.667 (8.92), 3.678 (4.81), 3.685 (5.07), 3.702 (4.38), 3.719 (1.27), 3.736 (5.97), 3.751 (11.35), 3.766 (5.81), 7.391 (2.32), 7.401 (2.11), 7.409 (5.12), 7.422 (4.01), 7.426 (5.17), 7.434 (4.38), 7.441 (4.38), 7.446 (2.75), 7.456 (4.49), 7.463 (4.44), 7.566 (1.80), 7.575 (2.80), 7.579 (2.80), 7.584 (2.80), 7.595 (4.70), 7.610 (1.69), 7.615 (2.90), 7.639 (2.53), 7.655 (2.85), 7.659 (3.01), 7.676 (3.06), 7.683 (3.38), 7.687 (3.43), 7.705 (2.85), 7.709 (2.59), 8.085 (5.17), 8.105 (4.54), 8.475 (13.36), 8.485 (6.97), 8.491 (6.86), 10.103 (6.23).
Example 146
ethyl 5-{8-fluoro-3-[3-{[2-(morpholin-4-yl)propanoyl]amino} -4-(trifluoromethoxy)phenyl]-4-oxo-3,4- dihydroquinazolin-7-yl}pyridine-3-carboxylate (enantiomer 1)
Figure imgf000255_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 1) (130 mg, 232 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (129 mg, 465 μmol), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (19.0 mg, 23.2 μιηοΐ) and sodium carbonate (98.5 mg, 930 μιηοΐ) in 1,4-dioxane (4.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 105°C overnight. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 73.0 mg (96 % purity, 48 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.86 min; MS (ESIpos): m/z = 630 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.65), 0.008 (1.90), 1.201 (10.38), 1.219 (10.57), 1.357 (7.48), 1.375 (16.00), 1.393 (7.69), 2.581 (2.95), 2.599 (1.16), 2.609 (0.72), 2.670 (0.42), 3.388 (0.91), 3.405 (3.00), 3.423 (2.95), 3.440 (0.81), 3.649 (4.30), 3.660 (7.55), 3.671 (4.39), 4.389 (2.35), 4.407 (7.36), 4.425 (7.25), 4.443 (2.25), 7.456 (2.35), 7.463 (2.39), 7.478 (2.74), 7.484 (2.86), 7.691 (2.16), 7.694 (2.25), 7.713 (1.88), 7.716 (1.74), 7.859 (1.76), 7.879 (2.30), 7.897 (2.04), 8.116 (3.48), 8.136 (2.90), 8.453 (4.39), 8.459 (4.34), 8.506 (8.59), 8.553 (3.44), 9.146 (3.79), 9.193 (4.71), 9.198 (4.69), 10.109 (4.55).
Example 147
ethyl 5 - { 8 -fluoro-3 - [3 - { [2-(morpholin-4-yl)propanoyl] amino } -4-(trifluoromethoxy)phenyl] -4- dihydroquinazolin-7-yl}pyridine-3-carboxylate (enantiomer 2)
Figure imgf000255_0002
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2- (morpholin-4-yl)propanamide (enantiomer 2) (130 mg, 232 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (129 mg, 465 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (19.0 mg, 23.2 μιηοΐ) and sodium carbonate (98.5 mg, 930 μιηοΐ) in 1,4-dioxane (4.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 105°C overnight. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 99.0 mg (95 % purity, 65 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.86 min; MS (ESIpos): m/z = 630 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.12), 0.008 (2.63), 1.201 (9.81), 1.219 (9.91), 1.357 (7.43), 1.375 (16.00), 1.393 (7.68), 2.366 (0.63), 2.523 (2.91), 2.569 (4.65), 2.580 (2.68), 2.599 (1.01), 2.609 (0.61), 2.670 (0.45), 2.710 (0.66), 3.388 (0.83), 3.405 (2.81), 3.423 (2.70), 3.440 (0.78), 3.649 (3.87), 3.660 (6.90), 4.389 (2.33), 4.407 (7.30), 4.425 (7.25), 4.443 (2.25), 7.456 (2.27), 7.462 (2.25), 7.478 (2.55), 7.484 (2.68), 7.691 (2.07), 7.694 (2.10), 7.712 (1.79), 7.716 (1.62), 7.859 (1.67), 7.876 (2.05), 7.879 (2.22), 7.897 (2.00), 8.116 (3.31), 8.137 (2.73), 8.453 (3.99), 8.459 (4.02), 8.506 (8.06), 8.553 (3.18), 9.146 (3.61), 9.193 (4.83), 9.198 (4.85), 10.108 (4.25).
Example 148
ethyl 5-{8-fluoro-3-[3-{[2-(l,4-oxazepan-4-yl)propanoyl]amino} -4-(trifluoromethoxy)phenyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate (enantiomer 1)
Figure imgf000256_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 1) (130 mg, 227 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (126 mg, 453 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (18.5 mg, 22.7 μιηοΐ) and sodium carbonate (96.1 mg, 907 μιηοΐ) in 1,4-dioxane (4.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 105°C overnight. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 100 mg (99 % purity, 69 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.58 min; MS (ESIpos): m/z = 644 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.70), 0.008 (1.89), 1.194 (10.11), 1.212 (10.24), 1.357 (7.37), 1.375 (16.00), 1.393 (7.61), 1.842 (0.67), 1.857 (1.93), 1.871 (2.70), 1.885 (2.15), 1.901 (0.78), 2.711 (0.98), 2.744 (5.61), 2.756 (4.93), 2.767 (1.61), 2.790 (0.54), 3.656 (2.98), 3.667 (5.72), 3.679 (3.13), 3.686 (3.22), 3.703 (2.76), 3.721 (0.85), 3.736 (3.83), 3.751 (7.28), 3.766 (3.74), 4.389 (2.28), 4.407 (7.15), 4.425 (7.13), 4.443 (2.22), 7.445 (2.37), 7.451 (2.35), 7.467 (2.63), 7.473 (2.76), 7.686 (2.04), 7.690 (2.13), 7.708 (1.78), 7.712 (1.65), 7.859 (1.67), 7.879 (2.24), 7.897 (1.93), 8.117 (3.37), 8.137 (2.78), 8.492 (4.39), 8.499 (4.41), 8.509 (8.52), 8.554 (3.28), 9.146 (3.61), 9.193 (4.80), 9.198 (4.80), 10.105 (4.17).
Example 149
ethyl 5-{8-fluoro-3-[3-{[2-(l,4-oxazepan-4-yl)propanoyl]amino} -4-(trifluoromethoxy)phenyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}pyridine-3-carboxylate (enantiomer 2)
Figure imgf000257_0001
A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(l,4- oxazepan-4-yl)propanamide (enantiomer 2) (130 mg, 227 μιηοΐ), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (126 mg, 453 μιηοΐ), [l,l-bis-(diphenylphosphino)-ferrocen]- dichloropalladium-dichloromethane -complex (18.5 mg, 22.7 μιηοΐ) and sodium carbonate (96.1 mg, 907 μιηοΐ) in 1,4-dioxane (4.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 105°C overnight. The reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 95:5 to 0: 100 followed by a preparative RP-HPLC 250x40mm with acetonitrile/water (0.1% formic acid) to afford 57.0 mg (99 % purity, 39 % yield) of the title compound.
LC-MS (Method 6): Rt = 1.58 min; MS (ESIpos): m/z = 644 [M+H]+
Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.38), 0.008 (1.63), 1.194 (9.51), 1.212 (9.68), 1.358 (7.28), 1.375 (16.00), 1.393 (7.54), 1.842 (0.60), 1.857 (1.77), 1.871 (2.42), 1.886 (1.98), 1.901 (0.75), 2.367 (0.58), 2.524 (1.47), 2.710 (1.14), 2.744 (5.06), 2.756 (4.48), 2.767 (1.45), 2.790 (0.47), 3.656 (2.64), 3.667 (5.20), 3.679 (2.85), 3.686 (3.03), 3.703 (2.64), 3.721 (0.75), 3.736 (3.61), 3.751 (6.91), 3.766 (3.54), 4.389 (2.21), 4.407 (7.16), 4.425 (7.07), 4.443 (2.17), 7.445 (2.35), 7.451 (2.33), 7.467 (2.59), 7.473 (2.68), 7.687 (1.89), 7.690 (2.01), 7.708 (1.72), 7.712 (1.56), 7.859 (1.59), 7.876 (1.93), 7.880 (2.07), 7.897 (1.86), 8.117 (3.10), 8.138 (2.54), 8.493 (4.25), 8.499 (4.27), 8.509 (8.33), 8.553 (2.98), 9.146 (3.24), 9.193 (4.78), 9.198 (4.78), 10.105 (3.85).
EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS Biological investigations
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.
Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein · the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and
• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values calculated utilizing data sets obtained from testing of one or more synthetic batch.
The in vitro activity of the compounds of the present invention can be demonstrated in the following assays: Biological assays:
B-1 Measurement of the inhibitory activity of selected compounds on the Wildtype Wnt signaling cascade: HEK293 TOP/FOP Assay In order to discover and characterize small molecules which inhibit the wildtype Wnt pathway, a cellular reporter assay was employed. The corresponding assay cell was generated by transfection of the mammalian cell line HEK293 (ATCC, #CRL-1573) with the Super TopFlash vector (Morin, Science 275, 1997, 1787-1790; Molenaar et al., Cell 86 (3), 1996, 391 -399). The HEK293 cell line is cultivated at 37°C and 5% C02 in DMEM (Life Technologies, #41965-039), supplemented with 2 mM glutamine, 20 mM HEPES, 1.4 mM pyruvate, 0.15% Na-bicarbonate and 10% foetal bovine serum (GIBCO, #10270). Stable transfectants were generated by selection with 300 μg/ml Hygromycin.
In a parallel approach, HEK293 cells were cotransfected with the FOP control vector and pcDNA3. The FOP vector is identical to the TOP construct, but it contains instead of functional TCF elements a randomized, non-functional sequence. For this transfection a stable transfected cell line was generated as well, based on selection with Geneticin (1 mg/ml).
In preparation of the assay, the two cell lines were plated 3 hrs before beginning the test at 10000 cells per well in a 384 micro titre plate (MTP) in 30 μΐ growth medium. Beforehand a dose response curve for the Wnt dependent luciferase expression was recorded by stimulating the assay cell line with human recombinant Wnt-3a (R&D, #5036-WN-010) at different concentrations for 44 hrs at 37°C and 5% C02 followed by subsequent luciferase measurement, to determine the Wnt-3a EC50 for the HEK293 TOP cell line, which corresponded to 150 ng/ml Wnt-3a. The recombinant human Wnt-3a was thereby applied as dilution series between 2500 and 5 ng/ml in two-fold dilution steps.
Selective inhibitory activity for small molecules on the wildtype Wnt pathway was determined after parallel incubation of both (TOP and FOP) HEK293 reporter cell lines with a compound dilution series from 50 μΜ to 15 nM in steps of 3.16-fold dilutions in CAFTY buffer (130 mM sodium chloride, 5 mM potassium chloride, 20 mM HEPES, 1 mM magnesium chloride, 5 mM sodium bicarbonate , pH 7.4) containing 2 mM Ca2+ and 0.01% BSA.
The compounds were thereby serially prediluted in 100%> DMSO and thereafter 50 fold into the CAFTY compound dilution buffer (described above). From this dilution 10 μΐ were added in combination with the EC50 concentration of recombinant Wnt3a to the cells in 30 μΐ growth medium and incubated for 44 hours at 37°C and 5%> CO2. Thereafter luciferase assay buffer (1 : 1 mixture of luciferase substrate buffer (20 mM Tricine, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 4 mM DTT, 270 μΜ Coenzyme A, 470 μΜ Luciferin, 530 μΜ ATP, ph adjusted to pH 7.8 with a sufficient volume of 5M sodium hydroxide) and Triton buffer (30 ml Triton X-100, 115 ml glycerol, 308 mg Dithiothreitol, 4.45 g disodium hydrogen phosphate ■ 2 H2O, 3.03 g Tris ■ HCL, ad 11 H2O, pH 7.8) was added in an equal volume to determine luciferase expression as a measure of Wnt signaling activity in a luminometer. The Wnt inhibitory activity was determined as IC50 of resulting dose response curves.
B-2 Measurement of the inhibitory activity of selected compounds on the D-catenin mutant Wnt signaling cascade: HCT116 TOP/FOP Assay
In order to discover and characterize small molecules which inhibit the constitutive ly active _ -catenin mutant Wnt pathway, a cellular reporter assay was employed. The corresponding assay cell was generated by transfection of the mammalian cell line HCT1 16 (ATCC, #CCL-247) with the Super TopFlash vector (Morin, Science 275, 1997, 1787-1790; Molenaar et al., Cell 86 (3), 1996, 391 -399). The HCT1 16 cell line is cultivated at 37°C and 5% C02 in DMEM/F12 (Life Technologies, #1 1320- 033), supplemented with 2 mM glutamine, 20 mM HEPES, 1.4 mM pyruvate, 0.15% Na-bicarbonate and 10% foetal bovine serum (GIBCO, #10270). Stable transfectants were generated by selection with 400 μg/ml Hygromycin.
In a parallel approach, HCT1 16 cells were cotransfected with the FOP control vector and pcDNA3. The FOP vector is identical to the TOP construct, but it contains instead of functional TCF elements a randomized, non-functional sequence. For this transfection a stable transfected cell line was generated as well, based on selection with Geneticin (1 mg/ml).
In preparation of the assay, the two cell lines were plated 3 hrs before beginning the test at 10000 cells per well in a 384 micro titre plate (MTP) in 30 μΐ growth medium. Selective inhibitory activity for small molecules on the ~~ -catenin Wnt pathway was determined after parallel incubation of both (TOP and FOP) HCT1 16 reporter cell lines with a compound dilution series from 50 μΜ to 15 nM in steps of 3.16-fold dilutions in CAFTY buffer (130 mM sodium chloride, 5 mM potassium chloride, 20 mM HEPES, 1 mM magnesium chloride, 5 mM sodium bicarbonate , pH 7.4) containing 2 mM Ca2+ and 0.01% BSA. The compounds were thereby serially prediluted in 100% DMSO and thereafter 50 fold into the CAFTY compound dilution buffer (described above). From this dilution 10 μΐ were added to the cells in 30 μΐ growth medium and incubated for 44 hours at 37°C and 5% CO2. Thereafter luciferase assay buffer (1 : 1 mixture of luciferase substrate buffer (20 mM Tricine, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 4 mM DTT, 270 μΜ Coenzyme A, 470 μΜ Luciferin, 530 μΜ ATP, ph adjusted to pH 7.8 with a sufficient volume of 5M sodium hydroxide) and Triton buffer (30 ml Triton X-100, 1 15 ml glycerol, 308 mg Dithiothreitol, 4.45 g disodium hydrogen phosphate ■ 2 H2O, 3.03 g Tris ■ HCL, ad 11 H2O, pH 7.8) was added in an equal volume to determine luciferase expression as a measure of Wnt signaling activity in a luminometer. The Wnt inhibitory activity was determined as IC50 of resulting dose response curves. Table 1: Assay results on inhibitory activity on the D-catenin mutant and wildtype Wnt signaling cascade
HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol/L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 1 4.50 E-8 1.30 E-8 Example 12 2.10 E-7 3.60 E-8
Example 2 3.30 E-8 4.70 E-8 Example 13 1.25 E-7 5.25 E-8
Example 3 1.15 E-7 2.95 E-8 Example 14 7.35 E-8 4.60 E-8
Example 4 9.30 E-8 5.45 E-8 Example 15 4.25 E-8 1.50 E-8
Example 5 2.00 E-8 1.44 E-8 Example 16 3.55 E-8 6.30 E-9
Example 6 4.60 E-8 1.40 E-8 Example 17 1.30 E-7 1.30 E-8
Example 7 1.00 E-7 3.20 E-8 Example 18 4.60 E-8 2.04 E-8
Example 8 9.40 E-8 2.30 E-8 Example 19 9.45 E-8 4.70 E-8
Example 9 6.50 E-8 6.30 E-8 Example 20 1.75 E-8 4.08 E-8
Example 10 1.19 E-7 2.85 E-8 Example 21 3.20 E-8 1.20 E-8
Example 11 1.50 E-7 8.80 E-8 Example 22 2.50 E-8 3.10 E-8 HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 23 7.50 E-8 5.65 E-8 Example 35 8.80 E-8 4.40 E-8
Example 24 8.55 E-8 4.30 E-8 Example 36 7.05 E-8 3.00 E-8
Example 25 4.00 E-8 2.50 E-5 Example 37 1.90 E-8 1.50 E-8
Example 26 2.30 E-8 7.10 E-9 Example 38 3.85 E-8 1.95 E-8
Example 27 1.10 E-7 4.85 E-8 Example 39 3.85 E-8 2.00 E-8
Example 28 4.00 E-8 1.30 E-8 Example 40 2.50 E-8 4.10 E-8
Example 29 2.25 E-8 8.30 E-9 Example 41 5.50 E-8 3.75 E-8
Example 30 2.00 E-6 1.20 E-7 Example 42 4.20 E-8 1.30 E-8
Example 31 7.45 E-8 3.20 E-8 Example 43 4.10 E-8 2.80 E-8
Example 32 3.40 E-8 1.50 E-8 Example 44 9.20 E-8 3.80 E-8
Example 33 5.60 E-8 3.90 E-8 Example 45 8.10 E-8 3.00 E-8
Example 34 5.50 E-8 4.95 E-8 Example 46 1.10 E-7 7.10 E-8 HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 47 1.17 E-7 5.80 E-8 Example 59 3.05 E-8 8.90 E-9
Example 48 5.60 E-8 1.60 E-8 Example 60 1.12 E-7 4.20 E-8
Example 49 3.45 E-8 3.60 E-8 Example 61 7.70 E-8 4.35 E-8
Example 50 9.65 E-8 2.55 E-8 Example 62 1.02 E-7 3.65 E-8
Example 51 7.20 E-8 2.30 E-8 Example 63 6.05 E-8 4.00 E-8
Example 52 1.20 E-7 1.00 E-7 Example 64 1.60 E-7 6.45 E-8
Example 53 1.25 E-7 5.05 E-8 Example 65 1.20 E-7 3.65 E-8
Example 54 5.10 E-8 3.50 E-8 Example 66 6.50 E-8 1.70 E-8
Example 55 8.90 E-7 7.30 E-7 Example 67 9.65 E-8 3.45 E-8
Example 56 3.45 E-7 1.55 E-7 Example 68 2.05 E-8 7.35 E-9
Example 57 2.20 E-8 1.20 E-8 Example 69 6.65 E-8 8.80 E-9
Example 58 1.43 E-7 4.40 E-8 Example 70 2.65 E-8 1.80 E-8 HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol/L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 71 3.75 E-8 1.02 E-8 Example 84 3.20 E-8 2.05 E-8
Example 72 1.95 E-8 8.90 E-9 Example 85 6.95 E-8 2.36 E-8
Example 73 7.20 E-8 1.85 E-8 Example 86 3.70 E-8 1.95 E-8
Example 74 4.50 E-8 1.04 E-8 Example 87 6.65 E-8 1.17 E-8
Example 75 7.20 E-8 2.00 E-8 Example 88 1.25 E-7 7.15 E-9
Example 76 3.85 E-7 2.30 E-7 Example 89 5.65 E-8 2.10 E-8
Example 77 2.15 E-7 1.51 E-7 Example 90 8.60 E-8 3.30 E-8
Example 78 3.20 E-7 4.20 E-7 Example 91 8.80 E-8 4.75 E-8
Example 80 4.25 E-8 1.6 E-8 Example 92 1.75 E-7 1.95 E-8
Example 81 2.95 E-8 1.2 E-8 Example 93 8.90 E-8 2.65 E-8
Example 82 4.45 E-8 2.35 E-8 Example 94 4.00 E-8 1.15 E-8
Example 83 2.25 E-8 1.30 E-8 Example 95 2.75 E-7 1.95 E-8 HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol/L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 96 6.20 E-8 1.75 E-8 Example 108 9.95 E-8 2.30 E-8
Example 97 3.69 E-8 1.34 E-8 Example 109 4.25 E-8 1.35 E-8
Example 98 9.40 E-8 8.10 E-8 Example 110 7.30 E-8 5.30 E-8
Example 99 2.09 E-8 1.55 E-8 Example 111 6.30 E-8 2.00 E-8
Example 100 7.92 E-9 7.35 E-9 Example 112 5.28 E-8 2.63 E-8
Example 101 1.27 E-8 9.75 E-9 Example 113 3.35 E-8 6.55 E-9
Example 102 8.93 E-8 1.68 E-8 Example 114 3.23 E-8 7.32 E-9
Example 103 6.35 E-8 1.12 E-8 Example 115 1.03 E-7 9.15 E-8
Example 104 2.10 E-8 8.20 E-9 Example 116 8.25 E-8 1.60 E-7
Example 105 1.45 E-8 5.00 E-9 Example 117 2.55 E-7 1.88 E-8
Example 106 2.60 E-8 1.25 E-8 Example 118 5.55 E-7 3.45 E-7
Example 107 4.55 E-8 1.45 E-8 Example 119 2.50 E-7 7.45 E-8 HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol/L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 120 1.81 E-7 9.92 E-8 Example 132 9.30 E-9 4.50 E-9
Example 121 3.85 E-7 2.75 E-7 Example 133 4.70 E-8 7.95 E-9
Example 122 3.00 E-7 3.20 E-7 Example 134 6.10 E-9 4.45 E-9
Example 123 2.50 E-8 6.30 E-9 Example 135 4.75 E-8 1.20 E-8
Example 124 1.46 E-7 1.79 E-8 Example 136 1.25 E-8 5.05 E-9
Example 125 8.10 E-9 2.30 E-8 Example 137 4.10 E-8 1.60 E-8
Example 126 2.50 E-9 6.00 E-8 Example 138 1.06 E-8 4.45 E-9
Example 127 2.05 E-9 1.60 E-8 Example 139 1.24 E-8 4.10 E-9
Example 128 1.40 E-8 3.65 E-9 Example 140 1.15 E-8 4.70 E-9
Example 129 1.10 E-8 4.10 E-9 Example 141 2.20 E-8 6.50 E-9
Example 130 6.10 E-9 3.30 E-9 Example 142 6.75 E-9 4.85 E-9
Example 131 1.65 E-8 6.90 E-9 Example 143 1.35 E-8 6.85 E-9 HEK293 HCT116 HEK293 HCT116
Example No TOPFlash TOPFlash Example No TOPFlash TOPFlash
ICso [mol/L] IC50 (mol/L) ICso [mol/L] IC50 (mol/L)
Example 144 3.20 E-8 1.18 E-8 Example 147 3.25 E-8 9.95 E-9
Example 145 1.95 E-8 1.55 E-8 Example 148 6.30 E-9 4.55 E-9
Example 146 6.55 E-9 4.10 E-9 Example 149 1.65 E-8 1.20 E-8
Biological in vivo assays
The in vivo activity of the compounds of the present invention can be demonstrated in the following assays:
B-3 BLEOMYCIN-INDUCED PULMONARY FIBROSIS MODEL (RODENTS) - SINGLE OR RECHALLENGE
Animal Model: Male Wistar WU rats or C57B16 mice are used, since these animals are well established as a model of idiopathic pulmonary fibrosis since following bleomycin or silica treatment, there is a good development of pulmonary fibrosis in the lungs in these animals. Male Wistar WU rats [Crl:WI(WU)] are supplied by Charles River Deutschland, Sulzfeld, at the age of 9 weeks. At start of the study (Day 0) the animals will be 10 weeks old. As to the mouse model, C57/BL6 mice (Charles River, Sulzfeld, Germany) aged 8-12 weeks, weighing 22-30 mg, are used in all experiments. Induction of lung fibrosis by bleomycin: Bleomycin aerosol is given intratracheally in mice or rats on Day 0 (and second dose on Day 14 in the rechallenge model) by means of an aerosolizer (Micro Sprayer® Aerosolizer - Model IA-1C-R for rats or Model IA-1C-M for mice). The tip of the device is gently inserted down the trachea of the anesthetized animal - near to, but not touching the carina (first bifurcation).The dose is equivalent to 1 U bleomycin (= ca. 4 U/kg in rats/mice), given in two doses with positioning of the animal on the left and then on the right side, respectively. Control animals receive 0.9% NaCl. Agents
Specification: bleomycin sulfate solution (Bleomedac ®)
Color:white to yellowish
Shape: Powder
Supplier: Medac GmbH, Wedel, Germany
Working solutions: aqueous solutions in 0.9% NaCl
Stability of solution: 7 days when cooled in refrigerator (ca. +5°C, sealed with cap) Vehicle for negative control group (i.tr. instead of bleomycin):
Specification: NaCl (physiological sodium chloride solution)
Color:clear (solution)
Shape: 0.9% aqueous solution
Supplier: Braun, Melsungen
Stability after opening: (taking by cannula trough rubber seal): 2 weeks when cooled in refrigerator (ca. +5°C).
Bleomycin-Induced Pulmonary Fibrosis Model (Rodents) - Single
In the single hit bleomycin-induced pulmonary fibrosis model, bleomycin is applied intratracheally at Day 0 (baseline) and treatment is initiated only after Day 10 in order to allow resolution of the acute inflammatory phase. All functional endpoints are recorded on Day 28 and animals are subsequently sacrificed for further ex -vivo biomarker measurements. Bleomycin-Induced Pulmonary Fibrosis Model (Rodents) - Rechallenge
In the rechallenge bleomycin-induced pulmonary fibrosis model, bleomycin is applied intratracheally twice: at Day 0 (first hit) and Day 14 (rechallenge), respectively. Treatment is initiated at Day 28 in order to allow animals to recover from second challenge with bleomycin. At week 10, all assessments are performed and animals subsequently sacrificed for further ex -vivo biomarker assessments.
SILICA-INDUCED PULMONARY FIBROSIS MODEL (RODENTS) - SINGLE OR RECHALLENGE
This model uses an identical setup like the bleomycin model, however using a DQ12 silica challenge. Induction of lung fibrosis by silica: Fibrosis induction: Rodents are treated intratracheally with high purity DQ12 Crystalline Silica 30 mg/rat and 2.5 mg/mouse. The administration volume was 10 ml/kg body weight. The control animals receive vehicle only. Readout for the BLEOMYCIN-INDUCED PULMONARY FIBROSIS MODEL as well as the SILICA-INDUCED PULMONARY FIBROSIS MODEL:
Mouse/Rat lung function is assessed by using a Forced Pulmonary Maneuver System (DSI Buxco Research Systems, Wilmington, NC, USA) following the manufacturer's protocols (Eur. J. Immunol 44, 3283-3294 (2014).). Dense lung parenchymal tissue is quantified by high-resolution computed tomography using the Skyscan 1178 micro-CT system (Kontich, Belgium). Detailed echocardiography is performed by using the FUJIFILM Visual Sonics Vevo 3100 system, focusing on assessment of both left and right-heart function. Lungs are further processed for detailed histological and biomarker analyses.

Claims

1. A compound of general formula (I):
Figure imgf000270_0001
in which
R1 represents a hydrogen atom, methyl or a halogen atom,
R2 represents a phenyl group or a 5- to 10-membered heteroaryl group,
where any phenyl group and any 5- to 10-membered heteroaryl group are each optionally substituted, identically or differently, with one, two or three groups selected from a halogen atom, (Ci-C i)-alkyl, amino, mono-(Ci-C4)-alkylamino, di-(Ci-C4)- alkylamino, hydroxy, cyano, (Ci-C4)-alkoxycarbonyl, (Ci-C4)-alkoxy and trifluoromethoxy,
where said (Ci-C4)-alkyl is optionally substituted with hydroxy or up to five fluorine atoms,
R3 represents a hydrogen atom, methyl or a halogen atom,
R4 represents a group selected from a hydrogen atom, (Ci-C4)-alkyl and (C3-C6)-cycloalkyl, where said (Ci-C4)-alkyl is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, cyclopropyl and optionally up to five fluorine atoms,
R5 represents a group selected from a hydrogen atom, and (Ci-C4)-alkyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen, or
R4 and R5 together with the carbon atom they are attached form a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,
where said 4- to 6-membered heterocycle is optionally substituted with one or two (Ci- C4)-alkyl groups and optionally up to four fluorine atoms, where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms where said 4- to 6-membered carbocycle is optionally substituted with one or two (Ci- C i)-aikyl groups and optionally up to four fluorine atoms,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
R6 represents #-NRuR12, a 5- or 6-membered heteroaryl group, di-(Ci-C4)-alkylamino or (Ci-C4)-alkoxycarbonylamino,
where
# represents the point of attachment to the carbon atom in alpha position to the carbonyl of the amide group,
Ru and R12 represent (Ci-C4)-alkyl,
where said (Ci-C4)-alkyl is optionally substituted with (Ci-C4)-alkoxy, or
R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono- or bicyclic azaheterocycle
where said 4- to 10-membered heterocycle is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, oxo and (Ci- C4)-alkyl,
where said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms
R7 represents a group selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methoxymethyl, 2,2,2-trifluoroethoxy, 2-methoxyethoxy and 2- hydroxypropan-2-yl,
R8 represents a hydrogen atom or fluorine,
R9 represents a hydrogen atom or fluorine,
R10 represents a hydrogen atom or fluorine,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1 , wherein
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000272_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13, R18, R22 and R26 represent a hydrogen atom, a halogen atom, (Ci-C i)-alkyl, trifluoromethyl, amino, hydroxyl or cyano,
R14, R19, R23 and R27 represent a hydrogen atom, a halogen atom, (Ci-C i)-alkyl, amino, hydroxy, cyano, (Ci-C i)-alkoxycarbonyl, (C1-C4)- alkoxy, difluoroalkoxy or trifluoromethoxy,
where said (Ci-C4)-alkyl is optionally substituted with up to three fluorine atoms,
R15, R20 and R24 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl, amino or hydroxy,
R16, R25 and R28 represents a hydrogen atom, a halogen atom, (Ci-C4)-alkyl, amino, hydroxy, cyano, (Ci-C4)-alkoxycarbonyl, (C1-C4)- alkoxy, difluoromethoxy or trifluoromethoxy,
where said (Ci-C4)-alkyl is optionally substituted with up to three fluorine atoms,
R17, R21 and R29 represents a hydrogen atom, a halogen atom, (Ci-C4)-alkyl, trifluoromethyl, amino, hydroxyl or cyano,
or
lH-pyrazol-4-yl,
where lH-pyrazol-4-yl is optionally substituted, identically or differently, with one or two groups selected from (Ci-C4)-alkyl, trifluoromethyl, difluoromethyl, amino, hydroxyl and cyano,
R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom, methyl and ethyl,
R5 represents a group selected from a hydrogen atom, methyl and ethyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen, or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring or an oxetane ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-5- azabicyclo[2.2.1]hept-5-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 2-oxa-5- azabicyclo[2.2.2]oct-5-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4- cyclopropylpiperazin-l-yl, 4-isopropylpiperazin-l -yl, 4-isobutylpiperazin-l-yl, 6- methyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-ethyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6- cyclopropyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-isopropyl-3,6-diazabicyclo[3.1.1 ]hept-
3- yl, 6-isobutyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 5-methyl-2,5-diazabicyclo[2.2.1 ]hept- 2-yl, 5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 5-isopropyl-2,5-diazabicyclo[2.2.1]hept-
2- yl, 5-isobutyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 5-cyclopropyl-2,5- diazabicyclo[2.2.1]hept-2-yl, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 8-ethyl-3,8- diazabicyclo[3.2.1]oct-3-yl, 8-cyclopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 8-isopropyl- 3,8-diazabicyclo[3.2.1]oct-3-yl, 8-isobutyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 5-methyl- 2,5-diazabicyclo[2.2.2]oct-2-yl, 5-ethyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5-isopropyl- 2,5-diazabicyclo[2.2.2]oct-2-yl, 5-isobutyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5- cyclopropyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl, 7- methyl-3,7-diazabicyclo[3.3.1]non-3-yl, 7-ethyl-3,7-diazabicyclo[3.3.1]non-3-yl,l,4- oxazepan-4-yl, 7-cyclopropyl-3 ,7-diazabicyclo [3.3.1 ]non-3 -yl, 7-isopropyl-3 ,7- diazabicyclo[3.3.1]non-3-yl, 7-isobutyl-3,7-diazabicyclo[3.3.1]non-3-yl, 1 ,4-oxazepan-
4- yl, 4-methyl-l,4-diazepan-l-yl, 4-ethyl-l,4-diazepan-l -yl , 4-cyclopropyl-l,4- diazepan-l -yl, 4-isopropyl-l,4-diazepan-l -yl, 4-isobutyl-l,4-diazepan-l -yl or (C1-C4)- alkoxycarbonylamino,
wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 2-oxa-5- azabicyclo[2.2.1]hept-5-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 2-oxa-5- azabicyclo[2.2.2]oct-5-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4- cyclopropylpiperazin-l-yl, 4-isopropylpiperazin-l -yl, 4-isobutylpiperazin-l-yl, 6- methyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-ethyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6- cyclopropyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 6-isopropyl-3,6-diazabicyclo[3.1.1 ]hept-
3- yl, 6-isobutyl-3,6-diazabicyclo[3.1.1 ]hept-3-yl, 5-methyl-2,5-diazabicyclo[2.2.1 ]hept- 2-yl, 5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 5-isopropyl-2,5-diazabicyclo[2.2.1]hept- 2-yl, 5-isobutyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 5-cyclopropyl-2,5- diazabicyclo[2.2.1]hept-2-yl, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 8-ethyl-3,8- diazabicyclo[3.2.1]oct-3-yl, 8-cyclopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 8-isopropyl- 3,8-diazabicyclo[3.2.1]oct-3-yl, 8-isobutyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 5-methyl- 2,5-diazabicyclo[2.2.2]oct-2-yl, 5-ethyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5-isopropyl- 2,5-diazabicyclo[2.2.2]oct-2-yl, 5-isobutyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 5- cyclopropyl-2,5-diazabicyclo[2.2.2]oct-2-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl, 7- methyl-3,7-diazabicyclo[3.3.1]non-3-yl, 7-ethyl-3,7-diazabicyclo[3.3.1]non-3-yl,l,4- oxazepan-4-yl, 7-cyclopropyl-3 ,7-diazabicyclo [3.3.1 ]non-3 -yl, 7-isopropyl-3 ,7- diazabicyclo[3.3.1]non-3-yl, 7-isobutyl-3,7-diazabicyclo[3.3.1]non-3-yl, 1 ,4-oxazepan- 4-yl, 4-methyl-l,4-diazepan-l-yl, 4-ethyl-l,4-diazepan-l -yl , 4-cyclopropyl-l,4- diazepan-l -yl, 4-isopropyl-l,4-diazepan-l -yl, 4-isobutyl-l,4-diazepan-l -yl are optionally substituted, identically or differently, with one or two groups selected from hydroxy, methyl, difluoromethyl and trifluoromethyl,
R7 represents a group selected from trifluoromethoxy, difluoromethoxy, methoxymethyl, 2,2,2-trifluoroethoxy, 2-methoxyethoxy and 2-hydroxypropan-2-yl,
R8 represents a hydrogen atom or fluorine,
R9 represents a hydrogen atom or fluorine,
R10 represents a hydrogen atom or fluorine,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
The compound according to claim 1 or 2, wherein:
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000274_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13, R18, R22 and R26 represent a hydrogen atom, fluorine or methyl,
R14, R19, R23 and R27 represent a hydrogen atom, chlorine, fluorine, (Ci- alkoxycarbonyl or methyl,
R15, R20 and R24 represent a hydrogen atom, (Ci-C i)-alkoxycarbonyl or amino,
R16, R25 and R28 represent a hydrogen atom, R17 and R21 represent a hydrogen atom,
R29 represents a hydrogen atom, fluorine or methyl,
or
1 -methyl- 1 H-pyrazol-4-yl,
R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom and methyl,
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen,
or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 8-oxa-3- azabicyclo[3.2.1 ]oct-3-yl, 4-methylpiperazin-l -yl, 6-methyl-3,6- diazabicyclo[3.1.1 ]hept-3-yl, 8-methyl-3,8-diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7- azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo-[3.3.1 ]non-3-yl, 4-methyl-l ,4- diazepan-l -yl, l ,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino,
wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl, 8-oxa-3- azabicyclo[3.2.1 ]oct-3-yl, 4-methylpiperazin-l -yl, 6-methyl-3,6- diazabicyclo[3.1.1 ]hept-3-yl, 8-methyl-3,8-diazabicyclo[3.2.1 ]oct-3-yl, 3-oxa-7- azabicyclo[3.3.1 ]non-7-yl, 7-methyl-3,7-diazabicyclo-[3.3.1 ]non-3-yl, 4-methyl-l ,4- diazepan-l -yl or l ,4-oxazepan-4-yl are optionally substituted with methyl,
R7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
R8 represents a hydrogen atom,
R9 represents a hydrogen atom,
R10 represents a hydrogen atom,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
4. The compound according to claim 1 , 2 or 3, of general formula (I):
R1 represents a hydrogen atom or fluorine,
R2 represents a group of the formula
Figure imgf000276_0001
where
# represents the point of attachment to the quinazolin-4(3H)-one core,
R13 and R18 represent a hydrogen atom, fluorine or methyl,
R14 and R19 represent a hydrogen atom, chlorine, fluorine, (C1-C4) alkoxycarbonyl or methyl,
R15 and R20 represent a hydrogen atom, (Ci-C4)-alkoxycarbonyl or amino,
R16 represents a hydrogen atom,
R17 and R21 represent a hydrogen atom,
with the provisio that no more than one of R13, R14, R15 is different from hydrogen, with the provisio that no more than one of R18, R19 and R20 is different from hydrogen, R3 represents a hydrogen atom or fluorine,
R4 represents a group selected from a hydrogen atom and methyl,
R5 represents a group selected from a hydrogen atom and methyl,
with the proviso that at least one of the radicals R4 and R5 is different from hydrogen, or
R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl ring,
R6 represents morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 8-oxa-3 azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin-l -yl, 6-methyl-3,6 diazabicyclo[3.1.1]hept-3-yl, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 3-oxa-7 azabicyclo[3.3.1]non-7-yl, 7-methyl-3,7-diazabicyclo-[3.3.1]non-3-yl, 4-methyl-l,4 diazepan-l -yl, l,4-oxazepan-4-yl or (Ci-C4)-alkoxycarbonylamino,
wherein morpholin-4-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, 8-oxa-3 azabicyclo[3.2.1]oct-3-yl, 4-methylpiperazin-l -yl, 6-methyl-3,6 diazabicyclo[3.1.1]hept-3-yl, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 3-oxa-7 azabicyclo[3.3.1]non-7-yl, 7-methyl-3,7-diazabicyclo-[3.3.1]non-3-yl, 1 ,4-oxazepan-4 yl or 4-methyl-l,4-diazepan-l-yl are optionally substituted with methyl, R7 represents a group selected from trifluoromethoxy, difluoromethoxy and methoxymethyl
R8 represents a hydrogen atom,
R9 represents a hydrogen atom,
R10 represents a hydrogen atom,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of.
A method of preparing a compound of general formula (I) according to any one of claims 1 to 4, said method comprising the step
[A] of allowing an intermediate compound of general formula (II)
Figure imgf000277_0001
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and,
X represents chlorine, bromine, iodine or triflate,
to react in the presence of a suitable inert solvent, with a compound of general formula
(III)
Figure imgf000277_0002
(ΠΙ),
in which R4 and R5 are as defined for the compound of general formula (I) as defined supra,
thereby giving a compound of general formula (IV)
Figure imgf000278_0001
in which R1, R3, R4, R5, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst, with an amine of general formula (V),
R11
HN R12
(V),
in which R11 and R12 are as defined for the compound of general formula (I) as defined supra,
thereby giving a compound of general formula (VI)
Figure imgf000278_0002
(VI),
in which R1, R3, R4, R5, R7, R8, R9, R10, R11 and R12 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst and a suitable base, with a boronic acid derivative of general formula (VII-A) or in the presence of a suitable Iridium-catalyst and a suitable base with a boronic acid derivative of general formula (VII -B),
Figure imgf000279_0001
thereby giving a compound of general formula (VIII)
Figure imgf000279_0002
(VIII),
in which R1, R3, R4, R5, R7, R8, R9, R10, R11 and R12 are as defined for the compound of general formula (I) as defined supra,
which is allowed to react in the presence of a suitable base and in the presence of a suitable catalyst, with a compound of general formula (IX),
R2
X1
(ix),
in which
X1 represents chlorine, bromine, iodine, mesylate, triflate or tosylate,
thereby giving a compound of general formula (I),
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
or
[B] of allowing an intermediate compound of general formula (II)
Figure imgf000280_0001
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
to react in the presence of a suitable inert solvent and where appropiate in the presence of a suitable base and where appropriate in the presence of a suitable amide coupling reagent, with a compound of general formula (X)
Figure imgf000280_0002
(X),
in which R4, R5 and R6 are as defined for the compound of general formula (I) as defined supra, and
X2 represents chlorine or hydroxy,
thereby giving a compound of general formula (VI),
which is then allowed to react according to the steps shown in [A] to give a compound of general formula (I), llowing an intermediate compound of general formula (II)
Figure imgf000280_0003
(Π), in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst, and a suitable base, with a boronic acid derivative of general formula (VII-A) or in the presence of a suitable Iridium-catalyst and a suitable base with a boronic acid derivative of general formula (VII-B),
Figure imgf000281_0001
thereby giving a compound of general formula (XI)
Figure imgf000281_0002
(xi),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra,
which is allowed to react in the presence of a suitable base and in the presence of a suitable catalyst, with a compound of general formula (IX),
R2
X1
(ix),
in which
X1 represents chlorine, bromine, iodine, mesylate, triflate or tosylate,
thereby giving a compound of general formula (XII)
Figure imgf000281_0003
(XII),
in which R1, R2, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra,
to react in the presence of a suitable inert solvent and where appropiate in the presence of a suitable base and where appropriate in the presence of a suitable amide coupling reagent, with a compound of general formula (X)
Figure imgf000282_0001
(X),
in which R4, R5 and R6 are as defined for the compound of general formula (I) as defined supra,
thereby giving a compound of general formula (I),
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
or
[D] of allowing an intermediate compound of general formula (II)
Figure imgf000282_0002
(Π),
in which R1, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra and
X represents chlorine, bromine, iodine or triflate,
which is allowed to react in the presence of a suitable base and where appropiate in the presence of a suitable catalyst, with a boronic acid derivative of general formula (VII-
C),
Figure imgf000283_0001
in which R: is as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (XII)
Figure imgf000283_0002
(XII),
in which R1, R2, R3, R7, R8, R9 and R10 are as defined for the compound of general formula (I) as defined supra,
which is then allowed to react according to the steps shown in [C] to give a compound of general formula (I),
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
A compound of general formula (I) according to any one of claims 1 to 4 for use in the treatment or prophylaxis of a disease.
A compound as defined in any of Claims 1 to 4 for use in a method for treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer.
Use of a compound of general formula (I) according to any one of claims 1 to 4 for the treatment or prophylaxis of a disease.
Medicament comprising a compound of general formula (I) according to any one of claims 1 to 4 and one or more pharmaceutically acceptable excipients.
Medicament comprising a compound as defined in any of Claims 1 to 4 in combination with one or more further active ingredients selected from the group consisting of serine / threonine / tyrosine kinase inhibitors and antifibrotic agents.
11. Medicament according to Claim 9 or 10 for treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer. 12. Method for treatment and/or prophylaxis of inflammatory and fibrotic pulmonary disorders and cardio-pulmonary disorders such as idiopathic pulmonary fibrosis, interstitial lung diseases, COPD, pulmonary arterial hypertension, bronchiolitis obliterans, asthma and allergic rhinitis, and lung cancer in humans and animals using an effective amount of at least one compound as defined in any of Claims 1 to 4, or of a medicament as defined in any of Claims 9 to 11.
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