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. Ca ²⁺ -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 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). 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/Ca ²⁺ 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 1 163237 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

in which

R ¹ represents a hydrogen atom, methyl or a halogen atom,

R ² represents a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle,

where any 3- to 7-membered carbocycle and any 4- to 7-membered heterocycle 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)-alkylcarbonyloxy, (Ci-C4)-alkoxycarbonylamino, mono- (Ci-C4)-alkylaminocarbonyloxy, di-(Ci-C4)-alkylaminocarbonyloxy, (Ci-C4)-alkoxy and trifluoromethoxy,

in which said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms, 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,

where said (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,

with the proviso that at least one of the radicals R ⁴ and R ⁵ is different from hydrogen, or

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-C i)-alkyl groups and optionally up to four fluorine atoms,

in which said (Ci-C i)-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-C i)-alkyl groups and optionally up to four fluorine atoms,

in which said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms R ⁶ represents #-NR ^u R ¹² , 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,

R ^u and R ¹² represent (Ci-C ₄ )-alkyl,

in which said (Ci-C4)-alkyl is optionally substituted with (Ci-C4)-alkoxy, or

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

in which said 4- to 10-membered azaheterocycle is optionally substituted, identically or differently, with one or two groups selected from hydroxy, (Ci-C4)-alkoxy, oxo and (C1-C4)- alkyl,

in which 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, trifluoromethoxymethyl, 2-methoxyethoxy, (C1-C4)- alkoxycarbonymethyl, 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,

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-C4-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" 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 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 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 SO ₂ 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[3.3.1]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[3.1.1]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, 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" and "5- to 10-membered heteroaryl" means a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 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, naphthyridinyl, 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-teri-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-C i)-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 teri-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-C4-alkyl" or "Ci-C4-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, 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 ;

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)- sulfonyljoxy, [(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 ² H (deuterium), ³ H (tritium), ^U C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ C1, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, 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 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. Depending on the desired sites of deuteration, in some cases 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. 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 :

1 H tautomer 3H tautomer

The present invention includes all possible tautomers of the compounds of the present invention as 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," 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 quartemary 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 hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydro lysed 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

R ¹ represents a hydrogen atom or fluorine,

R ² represents a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,

where any 3- to 6-membered carbocycle is optionally substituted with up to two fluorine atoms, where any 4- to 6-membered heterocycle is optionally substituted, identically or differently, with one or two groups selected from fluorine, (Ci-C i)-alkyl, hydroxy, amino, cyano, (C1-C4)- alkoxycarbonyl, (Ci-C i)-alkylcarbonyloxy, (Ci-C4)-alkoxycarbonylamino, mono-(Ci-C4)- alkylaminocarbonyloxy, di-(Ci-C4)-alkylaminocarbonyloxy, (Ci-C4)-alkoxy and trifluoromethoxy,

in which said (Ci-C4)-alkyl is optionally substituted with up to five fluorine atoms, R ³ represents a hydrogen atom or fluorine,

R ⁴ represents a group selected from methyl and ethyl,

where said methyl and ethyl are optionally substituted with up to three fluorine atoms,

R ⁵ represents a group selected from a hydrogen atom and methyl,

or

R ⁴ and R ⁵ together with the carbon atom 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-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- 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,

in which 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 and 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,

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,

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

R ¹ represents a hydrogen atom or fluorine, represents cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H- pyran-4-yl

where cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted with hydroxy, (C1-C4)- alkoxy, (Ci-C4)-alkoxycarbonylamino, (Ci-C4)-alkyl and optionally with up to two fluorine atoms,

in which (Ci-C4)-alkyl is optionally substituted with hydroxyl or amino,

or

represents a group of the formula

where

R ¹³ represents a hydrogen atom, (Ci-C4)-alkoxy, (Ci-C4)-alkoxycarbonylamino or hydroxy, R ¹⁴ represents a hydrogen atom or (Ci-C4)-alkyl,

R ¹⁵ represents a hydrogen atom, (Ci-C4)-alkoxy, (Ci-C4)-alkoxycarbonylamino or hydroxy,

R ¹⁶ represents (Ci-C4)-alkoxycarbonyl,

R ¹⁷ represents a hydrogen atom or (Ci-C4)-alkyl,

R ¹⁸ represents a hydrogen atom or (Ci-C4)-alkyl,

or

R ¹⁷ and R ¹⁸ together with the carbon atom they are attached represent a carbonyl group,

R ¹⁹ represents (Ci-C4)-alkoxycarbonyl,

R ²⁰ represents (Ci-C4)-alkoxycarbonyl,

R ²¹ represents (Ci-C4)-alkoxycarbonylamino, (Ci-C4)-alkoxy or hydroxy,

R ²² represents (Ci-C4)-alkoxycarbonylamino, (Ci-C4)-alkoxy or hydroxy,

represents a hydrogen atom,

represents methyl,

where said methyl is optionally substituted with up to three fluorine atoms, R ⁵ represents a group selected from a hydrogen atom and methyl,

or

R ⁴ and R ⁵ together with the carbon atom 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, in which 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 or l ,4-oxazepan-4-yl are optionally substituted with methyl,

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,

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 given to compounds of the formula (I) in which

R ¹ represents a hydrogen atom,

R ² represents cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or

represents a group of the formula

represents a hydrogen atom, methoxy or hydroxy, R ¹⁴ represents a hydrogen atom or methyl,

R ¹⁵ represents a hydrogen atom or hydroxy,

R ¹⁶ represents (Ci-C i)-alkoxycarbonyl,

R ¹⁷ represents a hydrogen atom,

R ¹⁸ represents a hydrogen atom,

or

R ¹⁷ and R ¹⁸ together with the carbon atom they are attached represent a carbonyl group,

R ¹⁹ represents (Ci-C i)-alkoxycarbonyl,

R ²⁰ represents (Ci-C i)-alkoxycarbonyl,

R ²¹ represents (Ci-C4)-alkoxycarbonylamino,

R ²² represents (Ci-C4)-alkoxycarbonylamino,

R ³ represents a hydrogen atom,

R ⁴ represents methyl,

R ⁵ represents a hydrogen atom,

or

R ⁴ and R ⁵ together with the carbon atom 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 or 4-methylpiperazin-l -yl,

R ⁷ represents a group selected from trifluoromethoxy, difluoromethoxy, 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.

Preference is also given to compounds of the formula (I) in which

R ¹ 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 R ² represents cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or

represents a group of the formula

where

R ¹³ represents a hydros *en atom, methoxy or hydroxy,

represents a hydros *en atom or methyl,

R ¹⁵ represents a hydros *en atom or hydroxy,

R ¹⁶ represents (Ci-C i)-alkoxycarbonyl,

R ¹⁷ represents a hydros *en atom,

represents a hydroj *en atom,

or

R ¹⁷ and R ¹⁸ together with the carbon atom they are attached represent a carbonyl group,

R ¹⁹ represents (Ci-C i)-alkoxycarbonyl,

R ²⁰ represents (Ci-C i)-alkoxycarbonyl,

R ²¹ represents (Ci-C4)-alkoxycarbonylamino,

R ²² represents (Ci-C4)-alkoxycarbonylamino,

and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.

Preference is also given to compounds of the formula (I) in which

R ³ 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

R ⁴ represents 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 R ⁵ represents a hydrogen atom,

with the proviso that at least one of the radicals R ⁴ and R ⁵ is different from hydrogen,

or

R ⁴ and R ⁵ 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

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:

R ⁴ and R ⁵ 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

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 or 4-methylpiperazin-l-yl,

and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.

Preference is also given to compounds of the formula (I) in which

R ⁶ represents morpholin-4-yl or 4-methylpiperazin-l-yl,

in which morpholin-4-yl or 4-methylpiperazin-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

R ⁷ represents a group selected from trifluoromethoxy, difluoromethoxy, methoxymethyl,

and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.

Preference is also given to compounds of the formula (I) in which

R ⁷ represents trifluoromethoxy,

and stereoisomers, tautomers, hydrates, solvates, and salts thereof, and mixtures of same.

Preference is also given to compounds of the formula (I) in which

R ⁷ represents difluoromethoxy,

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)

(Π),

in which 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,

to react in the presence of a suitable inert solvent, with a compound of general formula (III)

(ΠΙ),

in which R ⁴ and R ⁵ are as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (IV)

(IV),

in which 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,

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. . _^ 12

(V),

in which R ¹¹ and R ¹² are as defined for the compound of general formula (I) as defined supra, thereby giving a compound of general formula (VI)

(VI),

in which 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 and

X represents chlorine, bromine, iodine or triflate,

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 (VII), (VII),

in which

X ¹ represents hydrogen if X ¹ is attached to a nitrogen atom,

or

represents chlorine, bromine, iodine, mesylate, dimethoxyboryl, dihydroxyboryl, triflate or tosylate if X ¹ is attached to a carbon atom,

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)

(II),

in which 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,

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 (VIII)

(VIII),

in which R ⁴ , R ⁵ and R ⁶ are as defined for the compound of general formula (I) as defined supra, and X ² 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)

(Π),

in which 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,

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 (VII),

R ²

X ¹

(VII),

X ^I represents hydrogen if X ¹ is attached to a nitrogen atom,

or

represents chlorine, bromine, iodine, mesylate, dimethoxyboryl, dihydroxyboryl, triflate or tosylate if X ¹ is attached to a carbon atom,

thereby giving a compound of general formula (X),

(X),

in which 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,

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 (VIII),

(VIII),

in which R ⁴ , R ⁵ and R ⁶ are as defined for the compound of general formula (I) as defined supra, and

X ² represents chlorine or hydroxy,

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 (XV)

(xv),

in which R ¹ , R ² , 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 and

to react in the presence of (diethoxymethoxy)ethane, formic acid, NN-dimethylformamide (DMF), NN-dimethylacetamide (DMA) or NN-dimethylformamide dimethyl acetal, thereby giving a compound of general formula (I), The compounds of the formulae (III), (V), (VII) (VII) and (VIII) (VIII) are commercially available, known from the literature or can be prepared analogously to processes known from the literature. The compounds of the formulae (VIII) (VIII) in which X ² represents chlorine can be prepared from the corresponding carboxylic acids analogously to processes known from the literature.

The preparation processes can be illustrated in an exemplary manner by the synthesis schemes below (Schemes 1 to 2):

Scheme 1 :

[a): pyridine, dichloromethane, rt; b): Pd ₂ (dba)3 cBRIDP (cBRIDP = Di-tert-butyl(2,2-diphenyl-l- methyl-l -cyclopropyl)phosphine), cesium carbonate, dioxane, 80 °C].

Scheme 2:

[a): T3P, pyridine, 50°C; b): Pd/C, ¾, ethanol, tetrahydrofurane, rt, 1 atm; c): diethoxymethoxy)ethane, 120°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, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , T ¹ , T ² 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, 3 ^rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs. Suitable inert solvents for the process steps (II) + (III)→ (TV) and (II) + (VIII)→ (VI) and (X) + (VIII) — » ^■ (I) aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, diiso- propyl 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) + (VIII)→ (VI) and (X) + (VIII)→ (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.

Suitable condensing agents for the amide formation (II) + (VIII)—> (VI) and (X) + (VIII)—> (I) are, for example, carbodiimides such as NN'-diethyl-, NN'-dipropyl-, N,N'-diisopropyl-, N,N- dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1 ,2-oxazolium compounds such as 2-ethyl-5 -phenyl- 1 ,2-oxazolium 3 -sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-l -ethoxycarbonyl-l,2-dihydroquinoline or isobutyl chloroformate, propanephosphonic anhydride (T3P), l -chloro-N,N,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,N,N',N- tetramethyluronium tetrafluoroborate (TBTU), 0-(benzotriazol-l-yl)-N,NN',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-l-(2H)-pyridyl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TPTU), 0-(7-azabenzotriazol-l -yl)-N,NN',N'-tetramethyluronium hexafluorophosphate (HATU) or O- (lH-6-chlorobenzotriazol-l-yl)-l,l,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 T3P.

The process steps (II) + (III)→ (IV) and (II) + (VIII)→ (VI) and (X) + (VIII)→ (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). In general, standard pressure is employed.lt 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 (ΝΜΡ). 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)— »(I) and (II) + (VII)— » ^■ (X) 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-dimethoxyethane in a mixture with water, dimethylformamide, 1 ,4-dioxane and N-methylpyrrolidinone.

Suitable bases for the process step (VI) + (VII)— »(I) and (II) + (VII) — » ^■ (X)) 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 triethylamine, N-methylmorpholine, N-methyl- piperidine, 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 and potassium acetate.

Suitable Palladium catalysts for the process (VI) + (VII)— »(I) and (II) + (VII)— » ^■ (X) 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 l,4-Bis(diphenylphosphino)butane-palladium(II) chloride (Pd(dppb)Ch); Dichloro[l,3-bis(diphenylphosphino)propane]palladium(II) (Pd(dppp)Ch), [l,l '-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'-triisopropy l-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 (fert-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- 1,1 '-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,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,l '-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalyst) and 2- (dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl- l,l '-biphenyl (BrettPhos).

The process steps (VI) + (VII)→(I) and (II) + (VII)— » ^■ (X) 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.

For the processes (VI) + (VII)→(I) and (II) + (VII)→ (X) if X ¹ of (VII) represents chlorine, bromine, iodine, mesylate, triflate or tosylate and X ¹ is attached to a carbon atom of R ² , the reaction is carried out under Photochemistry reaction conditions in EvoluChemTM Photochemistry reactors with irradiation from a 34 W blue Kessil lamp (λ« = 455 nm). Fan cooling is used to regulate the reaction temperature

Inert solvents for the process step (XV)—> (I) are diethoxymethoxy) ethane, formic acid, NN-dimethyl- formamide (DMF), NN-dimethylacetamide (DMA) or DMF in a mixture with DMA. Preference is given to using diethoxymethoxy)ethane,

The process step (XV)— » ^■ (I) is 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.

The compounds of the formula (II) can be prepared by

[E] reacting a compound of the formula (XI),

in which 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,

and

T ³ represents tert-butyl,

to react in the presence of a suitable inert solvent, with an amine of general formula (XII),

in which R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined for the compound of general formula (I) as defined supra,

thereby giving a compound of general formula (XIII),

in which 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,

and

T ³ represents tert-butyl, which is allowed to react with diethoxymethoxy)ethane, formic acid, NN-dimethylformamide (DMF), NN-dimethylacetamide (DMA) or DMF in a mixture with DMA thereby giving a compound of the formula (XIV),

which 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, or

[F] reacting a compound of the formula (XVI),

(XVI),

in which R ¹ , R ² and are as defined for the compound of general formula (I) as defined supra, and

X represents chlorine, bromine, iodine or triflate,

and

T ² represents (Ci-C i)-alkyl,

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 (VII),

R ²

* ¹

(VII), in which

X ¹ represents hydrogen if X ¹ is attached to a nitrogen atom,

or

represents chlorine, bromine, iodine, mesylate, dimethoxyboryl, dihydroxyboryl, triflate or tosylate if X ¹ is attached to a carbon atom,

thereby giving a compound of general formula (XVII),

(XVII),

in which R ¹ , R ² and R ³ are as defined for the compound of general formula (I) as defined supra, and

T ² represents (Ci-C i)-alkyl, followed by cleavage of the ester by methods known to those skilled in the art, and then allowing the resulting compound of the formula (XVIII),

(XVIII),

in which R ¹ , R ² and R ³ 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 (XIX),

(XIX),

in which 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,

thereby giving a compound of general formula (XX),

(XX),

in which R ¹ , R ² , 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 and

whichis allowed to react with a suitable reducing agent to reduce the nitro group to an amino group,

thereby giving compounds of the formulae (XV) 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 compounds of the formula (XIX) can be prepared by

[G] reacting a compound of the formula (XXI),

(XXI),

in which R ⁴ and R ⁵ , are as defined for the compound of general formula (I) as defined supra, in a suitable inert solvent and where appropiate in the presence of a suitable base and where appropriate in the presence of a potassium iodide or halogen salts of quaternary ammonium, with a compound of general formula (V),

R"

H N _r 12 thereby giving a compound of general formula (XXII),

in which R ⁴ , R ⁵ , R ¹¹ and R ¹² 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 (XXIII),

(XXIII),

in which R ⁷ , R ⁸ , R ⁹ and R ¹⁰ and are as defined for the compound of general formula (I) as defined supra,

and represents chlorine, bromine, iodine or triflate,

thereby giving a compound of general formula (XXIV),

in which 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,

which is allowed to react with a suitable reducing agent to reduce the nitro group to an amino group,

thereby giving compounds of the formulae (XIX) 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 processes described are illustrated in an exemplary manner by the schemes below (Scheme 3-5)

[a): PYBOP, diisopropylamine, DMF, r.t.; b): formic acid, reflux; c): T1CI3, HCl, water, THF, 25-30 °C].

Scheme 4:

[a):Pd2(dba)3, cesium carbonate, Xantphos, dioxane, 80°C; b): cesium carbonate,methanol/water, r.t.].

Scheme 5:

[a):potassium carbonate, potassium iodide, acetonitrile, 70°Ct.; b): Pd2(dba)3, cesium carbonate, Xantphos, dioxane, 80°C; c): Pd/C, ethanol/tetrahydrofuran, r.t, 1 atm hydrogen.].

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 (XI) + (XII)→ (XIII) and (XVIII) + (XIX)→(XX) 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 (ΝΜΡ). 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 (XI) + (XII)→ (XIII) and (and (XVIII) + (XIX) →(XX) 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 (CDI), 1 ,2-oxazolium compounds such as 2-ethyl-5 -phenyl- 1 ,2-oxazolium 3 -sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-l -ethoxycarbonyl-l,2-dihydroquinoline or isobutyl chloroformate, 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), 0-(benzotriazol-l-yl)-NNN',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-l-(2H)-pyridyl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TPTU), 0-(7-azabenzotriazol-l -yl)-N,NN',N'-tetramethyluronium hexafluorophosphate (HATU) or O- (lH-6-chlorobenzotriazol-l-yl)-l,l,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 T3P.

The condensation (XI) + (XII)→ (XIII) and (XVIII) + (XIX)→(XX) are 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.

Alternatively, the carboxylic acid of the formula (XI) and (XVIII) 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 (XII) and (XIX), respectively, 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.

The process (XIII)— »(XIV) is generally carried out in a temperature range of from +60°C to +180°C, preferably from 30°C to +120°C. Suitable inert solvents for the process step (XrV)→(II) and (XX)→(XV) and (XXiV)→(XIX) 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 tert-butyl ether, 1 ,2-dimethoxyethane, bis-(2-methoxyethyl) ether, tetrahydrofuran or 1,4-dioxane, or dipolar aprotic solvents such as acetonitrile, NN-dimethyl- formamide (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 (XIV)→(II) and (XX)→(XV) and (XXrV)→(XIX) are for example Tin(II) chloride, Titanium (III) chloride, Iron(III) chloride, Titanium(IV) chloride, Tin, Iron, Zinc, Indium, Aluminum, Nickel or suitable catalysts, for example, palladium/carbon, palladium(II) hydroxide/carbon, platinum(IV) oxide, platinum and Raney nickel in a hydrogen atmosphere; preference is given to palladium/carbon in a hydrogen atmosphere .

The reaction is carried out generally within a temperature range from 0°C to +120°C, preferably at +20°C to +80°C.

The process (XIV)→(II) and (XX)→(XV) and (XXIV)→(XIX) are generally carried out in a temperature range of from -80°C to +220°C, preferably from -10°C to +100°C.

Suitable inert solvents for the process steps (XVI) + (VII)→(XVII) and (XXII) + (XXIII)→(XXIV) 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-dimethyl- acetamide (DMA), dimethyl sulfoxide (DMSO), NN-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (ΝΜΡ) or pyridine. It is also possible to use mixtures of the solvents mentioned. Preference is given to using 1,4-dioxane.

Suitable bases for the process step (XVI) + (VII)→(XVII) and (XXII) + (XXIII)→(XXIV) 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 triethylamine, N-methylmorpholine, N-methyl- piperidine, 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 and potassium acetate.

Suitable Palladium catalysts for the process (XVI) + (VII)→(XVII) and (XXII) + (XXIII)→(XXTV) 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'-triisopropy l-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- 1,1 '-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,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,l '-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalyst) and 2- (dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl- l,l '-biphenyl (BrettPhos).

The process steps (XVI) + (VII)→(XVII) and (XXII) + (XXIII)→(XXIV) 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. For the processes (XVI) + (VII)→(XVII) and (XXII) + (XXIII)→(XXIV) if X ¹ of (VII) and (XXIII) represent chlorine, bromine, iodine, mesylate, triflate or tosylate and X ¹ is attached to a carbon atom of R ² , the reaction is carried out under Photochemistry reaction conditions in EvoluChemTM Photochemistry reactors with irradiation from a 34 W blue Kessil lamp ^ _max = 455 nm). Fan cooling is used to regulate the reaction temperature

Suitable inert solvents for the process step (XXI) + (V)— »(XXII) for example, 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 (ΝΜΡ). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile and Ν,Ν-dimethylformamide or mixtures of these solvents.

Suitable bases for the process step (XXI) + (V)— »(XXII) 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 potassium carbonate.

Suitable catalysts for the process step (XXI) + (V)— »(XXII) 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 sodium iodide or potassium iodide. The amine coupling (XXI) + (V)— »(XXII) 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).

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. 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-myofibroblast 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.

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:

Boc tert-butyloxycarbonyl cBRIDP Di-tert-butyl(2,2-diphenyl- 1 -methyl- 1 -cyclopropyl)phosphine

Ex. Example d day(s)

TLC thin-layer chromatography

DCI direct chemical ionization (in MS)

DIEA NN-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF NN-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-trioxatriphosphorinane-2,4,6-tri oxide

Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

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), ... , δ _η (intensity _n ).

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%.

In the intermediates and working examples described hereinafter, a "2RS" identifier in the IUPAC name of the example in question, in conjunction with the term "racemate", means that this is a racemic mixture of the 2R enantiomer (—> 1st letter after the position number in "2R5") with the corresponding 2S enantiomer (—> 2nd letter after the position number). The "2RS" identifier in conjunction with the statements "diastereomer 1 " and "diastereomer 2" means that these are the two diastereomers in separate, isolated form, without having undertaken an assignment of the absolute configuration (2R or 25) to these diastereomers at the stereogenic center C-2. The "2RS" identifier in conjunction with the statements "enantiomer 1 " and "enantiomer 2" means that these are the two enantiomers in separate, isolated form, without having undertaken an assignment of the absolute configuration (2R or 25) to these enantiomers. Similar identifiers such as "2SR" that arise from the altered priority and/or sequence of named constituents owing to the IUPAC nomenclature rules should be interpreted in an analogous manner according to these instructions.

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 μηι x 0.33 μηι; 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 mL/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 μνα; 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.

Microwave: The microwave reactor used was a "single-mode" instrument of the Emrys™ Optimizer type.

Photochemistry: Photochemistry reactions were run in EvoluChemTM Photochemistry reactors with irradiation from a 34 W blue Kessil lamp (l _mx = 455 nm). Fan cooling was used to regulate the reaction temperature.

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" or "x Aqueous hydrochloric acid", "x CF3COOH", "x Na ⁺ " 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)carbam ate

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): R _t = 1.71 min; MS (ESIneg): m/z = 520 [M-H] ^"

Intermediate 2

7-Bromo -3 - [3 -nitro -4 -(trifluoromethoxy)phenyl] quinazolin

tert-Butyl (5-bromo-2-{[3-nitro-4-(trifluoromethoxy)phenyl]carbamoyl}ph enyl)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): R _t = 2.11 min; MS (ESIpos): m/z = 432 [M+H] ⁺

Intermediate 3

3 - [3 -Amino-4-(trifluoromethoxy)phenyl] -7-bromoquinazolin

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): R _t = 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

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(3 H)-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): R _t = 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

N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-2-chloropropanamide

(racemate)

A suspension of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromoquinazolin-4(3 H)-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): R _t = 2.06 min; MS (ESIpos): m/z = 490 [M+H] ⁺

Ή- MR (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 6

N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-2-(morpholin-4- yl)propanamide (racemate)

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): R _t = 1.86 min; MS (ESIpos): m/z = 541 [M+H] ⁺

Ή- MR (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 7

N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-2-(8- azabicyclo[3.2.1]oct-3-yl)propanamide (racemate)

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), 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): R _t = 2.16 min; MS (ESIpos): m/z = 567 [M+H] ⁺

Ή- MR (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 8

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)

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), 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 the title product. 63.0 mg (23 % yield).

LC-MS (Method 6): R _t = 1.79 min; MS (ESIpos): m/z = 553 [M+H] ⁺

Ή- MR (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 9

N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(4-methylpiperazin-l - yl)cyclopropanecarboxamide 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): R _t = 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 10

N-[5-(7-Bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-2-(4-methylpiperazin-l - yl)propanamide (racemate)

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): R _t = 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 11

tert-Butyl 4- {3-[3-amino-4-(trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroqui nazolin-7-yl}piperidine-l- carboxylate

4,4'-Di-tert-butyl-2,2'-bipyridine (6.71 mg, 25.0 μηιοΐ) and (l,2-Dimethoxyethane)nickel dichloride (CAS 29046-78-4) (5.49 mg, 25.0 μιηοΐ) were charged under argon in a flask and suspended in dry 1,2- dimethoxyethane (2.0 ml). This mixture was sonicated for 5 min. In a separated microwave vial under argon Iridium(l+), [4,4'-bis(l ,1 -dimethylethyl)-2,2'-bipyridine-KNl ,κΝΙ ']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (28.0 mg, 25.0 μιηοΐ), 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromoquinazolin- 4(3H)-one (200 mg, 500 μιηοΐ), tert-butyl 4-bromopiperidine-l-carboxylate (198 mg, 750 μmol), 1,1,1, 3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (150 μΐ, 500 μmol) and lithium hydroxide (23.9 mg, 1000 μιηοΐ) were dissolved in 1 ,2-dimethoxyethane (4.0 ml). Half of the solution of the first flask (catalyst mix) was added to the microwave vial mixture and an argon stream was passed through the resulting mixture. Then the reaction was stirred at rt for 22 h while irradiated with a 34W blue LED lamp in the EvoluChem™ Photochemistry Device at a distance of 7 cm. The reaction mixture was then charged completely on a silica gel column and a chromatographic separation was performed with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then purified by preparative RP-HPLC on a 125x30mm column (0.1% formic acid/acetonitrile gradient) to provide 65.0 mg (26 % yield) of the title product.

LC-MS (Method 6): R _t = 2.18 min; MS (ESIpos): m/z = 505 [M+H] ⁺

Ή-ΝΜΡν (500 MHz, DMSO-d6) δ [ppm] : 1.429 (16.00), 1.821 (0.44), 5.728 (1.22), 6.649 (0.55), 6.654 (0.55), 6.666 (0.54), 6.671 (0.57), 6.886 (1.07), 6.891 (1.00), 7.259 (0.41), 7.262 (0.41), 7.507 (0.46), 7.510 (0.47), 7.523 (0.46), 7.526 (0.49), 7.569 (0.94), 7.572 (0.81), 8.109 (0.93), 8.125 (0.84), 8.299 (2.28).

Intermediate 12

2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)propanamide (racemate)

2-Chloropropanamide (racemate) (250 mg, 98 % purity, 2.28 mmol) was disolved in DMF (7.3 ml) and treated with triethylamine (350 μΐ, 2.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (284 mg, 2.51 mmol) and potassium iodide (75.6 mg, 456 μιηοΐ). This mixture was heated at 50°C under argon for 3 days. After cooling to rt, the solvent was removed under reduced pressure and the residue was purified by chromatography through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15 to deliver 229 mg (96 % purity, 52 % yield) of the title compound.

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.030 (15.74), 1.048 (16.00), 1.500 (1.11), 1.517 (1.12), 1.670 (2.17), 1.689 (3.58), 1.707 (2.64), 1.730 (0.44), 1.835 (0.59), 1.861 (4.48), 1.873 (2.35), 1.878 (2.22), 1.890 (3.99), 1.913 (0.47), 2.298 (1.97), 2.302 (2.01), 2.325 (3.17), 2.329 (3.18), 2.388 (1.42), 2.392 (1.49), 2.415 (6.95), 2.445 (5.40), 2.474 (1.49), 2.803 (1.21), 2.820 (3.87), 2.837 (3.75), 2.855 (1.13), 4.181 (2.22), 4.192 (3.39), 4.203 (2.22), 6.973 (1.57), 7.045 (1.58).

Intermediate 13

N-[5-Nitro-2-(trifluoromethoxy)phenyl]-2-(8-oxa-3-azabicyclo [3.2.1]oct-3-yl)propanamide (racemate)

A mixture of 2-bromo-4-nitrophenyl trifluoromethyl ether (204 mg, 714 μιηοΐ), 2-(8-oxa-3- azabicyclo[3.2.1]oct-3-yl)propanamide (racemate) (151 mg, 96 % purity, 785 μιηοΐ), tris(dibenzylidenacetone)dipalladium (65.4 mg, 71.4 μιηοΐ), Xantphos (82.6 mg, 143 μιηοΐ) and cesium carbonate (698 mg, 2.14 mmol) was suspended in dioxane (7.1 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated at 100°C for 16 h. After cooling to rt, the reaction mixture was filtered through a silica column eluting with a mixture of dichloromethane/methanol 90: 10. The organic phase was then washed with water and, after phase separation, the organic layer was filtered through a water-removing filter. The filtrate was evaporated and purified by silica gel chromatography eluting with a gradient of cyclohexane:ethyl acetate from 95 :5 to 50:50 to provide 271 mg (97 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.02 min; MS (ESIpos): m/z = 390 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.30), 0.008 (1.97), 1.168 (15.83), 1.185 (16.00), 1.398 (14.98), 1.789 (4.17), 1.802 (2.38), 1.822 (0.61), 1.838 (0.65), 1.888 (1.07), 1.914 (2.10), 1.931 (1.41), 1.970 (1.49), 1.985 (1.96), 2.010 (0.76), 2.328 (0.40), 2.367 (0.40), 2.404 (1.01), 2.470 (1.12), 2.475 (1.22), 2.591 (9.28), 2.670 (0.49), 2.710 (0.40), 3.345 (1.31), 3.362 (4.27), 3.379 (4.22), 3.397 (1.15), 4.256 (4.24), 7.725 (2.57), 7.730 (2.52), 7.743 (1.27), 7.748 (2.99), 7.753 (2.81), 8.069 (4.21), 8.076 (4.19), 8.092 (3.63), 8.099 (3.71), 9.185 (6.50), 9.192 (6.44), 9.831 (4.82). Intermediate 14

N-[5-Amino-2-(trifluoromethoxy)phenyl]-2-(8-oxa-3-azabicyclo [3.2.1]oct-3-yl)propanamide (racemate)

N-[5-Nitro-2-(trifluoromethoxy)phenyl]-2-(8-oxa-3-azabicy clo[3.2.1]oct-3-yl)propanamide (racemate) (270 mg, 680 μιηοΐ) was disolved in ethanol (8.0 ml). Pd/C 10% (27.0 mg) was added and the reaction mixture was hydrogenated under atmospheric pressure overnight. The reaction mixture was then filtered over celite rinsing with ethanol. The residue was evaporated and dried under high vacuum to deliver 233 mg (95 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.49 min; MS (ESIpos): m/z = 360 [M+H] ⁺

Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 0.005 (0.75), 1.057 (0.49), 1.134 (15.87), 1.146 (16.00), 1.770 (1.99), 1.774 (2.20), 1.781 (4.06), 1.791 (2.59), 1.812 (0.40), 1.885 (0.74), 1.901 (3.86), 1.913 (2.91), 1.922 (3.12), 1.939 (0.60), 2.404 (0.59), 2.408 (0.65), 2.445 (0.60), 2.448 (0.59), 2.514 (0.65), 3.158 (1.27), 3.169 (4.39), 3.181 (4.32), 3.192 (1.23), 4.238 (2.26), 4.247 (2.97), 4.250 (2.97), 4.259 (2.26), 5.355 (9.88), 6.301 (3.50), 6.306 (3.56), 6.316 (3.63), 6.320 (3.69), 7.012 (2.66), 7.014 (2.78), 7.026 (2.62), 7.028 (2.64), 7.466 (5.69), 7.470 (5.75), 9.240 (4.86). Inter mediate 15

tert-Butyl 4-[4-(methoxycarbonyl)-3-nitrophenyl]piperazine-l -carboxylate

3

A mixture of methyl 4-bromo-2-nitrobenzoate (2.70 g, 10.4 mmol), tert-butyl piperazine-l -carboxylate (3.48 g, 18.7 mmol), tris(dibenzylidenacetone)dipalladium (951 mg, 1.04 mmol), Xantphos (1.20 g, 2.08 mmol) and cesium carbonate (10.1 g, 31.1 mmol) was suspended in dioxane (100 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 18 h. After cooling to rt, the reaction mixture was filtered through celite and the filter cake was washed with dichloromethane. The organic filtrate was washed with water and after phase separation, the organic layer was filtered over a water-removing filter and evaporated under reduced pressure. The residue was purified by chromatography over a silica column eluting with a gradient of cyclohexane/ethyl acetate from 100:0 to 60:40 to deliver 3.47 g (92 % purity, 84 % yield) of the title compound.

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.335 (0.81), 1.422 (16.00), 3.316 (2.77), 3.415 (0.88), 3.426 (1.66), 3.440 (1.51), 3.451 (0.76), 5.754 (0.49), 7.127 (0.42), 7.133 (0.42), 7.145 (0.43), 7.150 (0.44), 7.325 (0.92), 7.330 (0.84), 7.755 (1.12), 7.772 (1.02).

Intermediate 16

4-[4-(tert-Butoxycarbonyl)piperazin-l-yl]-2-nitrobenzoic acid

tert-Butyl 4-[4-(methoxycarbonyl)-3-nitrophenyl]piperazine-l-carboxylat e (3.47 g, 92 % purity, 8.74 mmol) was disolved in methanol (170 ml) and treated with cesium carbonate (5.69 g, 17.5 mmol) and water (33 ml). This mixture was heated at 40°C for 24 h. Half of the volume of methanol was then evaporated under reduced pressure and the rest of the solution was treated with a pH 5 aqueous buffer. The aqueous phase was then extracted three times with ethylacetate. The combined organic layers were then dried over sodium sulfate, filtered and evaporated to a volume of ca. 10 mL. 20 mL Diethyl ether were added to this solution and the mixture was stirred for 10 min. The suspension was then filtered and the solid was washed with diethyl ether. After drying under vacuum, 2.24 g (96 % purity, 70 % yield) of the title compound was obtained. Additionally, the filtrate was evaporated and the residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15 to provide 550 mg (96 % purity, 17 % yield) of the title compound.

LC-MS (Method 1): R _t = 0.91 min; MS (ESIneg): m/z = 350 [M-H] ^"

Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.175 (0.44), 1.420 (16.00), 1.988 (0.80), 3.386 (1.04), 3.397 (0.98), 3.432 (1.04), 3.438 (0.96), 3.444 (1.00), 7.257 (0.40), 7.261 (0.67), 7.266 (0.41), 7.741 (0.51), 7.743 (0.58), 7.759 (0.48), 7.761 (0.52).

Intermediate 17

tert-Butyl 4-(3 -nitro-4- { [3 - { [2-(8-oxa-3 -azabicyclo[3.2.1] oct-3-yl)propanoyl] amino} -4- (trifluoromethoxy)phenyl]carbamoyl}phenyl)piperazine-l-carbo xylate (racemate)

4-[4-(tert-Butoxycarbonyl)piperazin-l-yl]-2-nitrobenzoic acid (83.0 mg, 93 % purity, 220 μιηοΐ) and N- [5 -amino -2 -(trifluoromethoxy)phenyl] -2-(8-oxa-3 -azabicyclo [3.2.1] oct-3 -yl)propanamide (racemate) (94.7 mg, 264 μιηοΐ) were disolved in pyridine (1.5 ml) and treated with a solution of T3P (50% in ethyl acetate) (390 μΐ, 50 % purity, 660 μιηοΐ). The mixture was stirred at 50°C for 30 min and then it was directly submitted to preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to provide 100 mg (66 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m/z = 693 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.150 (2.11), 1.168 (2.15), 1.428 (16.00), 1.787 (0.59), 1.798 (0.43), 1.920 (0.49), 1.956 (0.43), 2.445 (1.44), 2.566 (1.55), 3.251 (0.61), 3.269 (0.62), 3.346 (0.88), 3.357 (1.43), 3.371 (1.32), 3.461 (1.21), 3.475 (1.35), 3.486 (0.82), 4.256 (0.74), 7.282 (0.41), 7.288 (0.44), 7.420 (0.47), 7.424 (0.44), 7.469 (0.88), 7.475 (0.84), 7.563 (0.42), 7.569 (0.42), 7.617 (0.85), 7.639 (0.74), 8.538 (0.74), 8.544 (0.74), 9.513 (1.01), 10.670 (1.13).

Intermediate 18

tert-Butyl 4-(3-amino-4- {[3- {[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanoyl]amino}-4- (trifluoromethoxy)phenyl]carbamoyl}phenyl)piperazine-l-carbo xylate (racemate)

tert-butyl 4-(3-nitro-4-{[3- {[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanoyl]amino}-4-(t rifluoro- methoxy)phenyl]carbamoyl}phenyl)piperazine-l -carboxylate (racemate) (100 mg, 144 μηιοΐ) was suspended in ethanol (5.0 ml) and THF (2.0 ml). Pd/C 10% (10.0 mg) was added and the reaction mixture was hydrogenated under atmospheric pressure overnight. The reaction mixture was then filtered over celite rinsing with ethanol. The residue was evaporated and dried under high vacuum to deliver 94.6 mg (100 % purity, 99 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.27 min; MS (ESIneg): m/z = 661 [M-H] ^"

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.59), 0.008 (0.63), 1.055 (0.49), 1.156 (2.15), 1.174 (2.17), 1.356 (1.17), 1.424 (16.00), 1.787 (0.60), 1.926 (0.52), 1.960 (0.44), 2.449 (1.43), 2.566 (1.47), 3.166 (0.90), 3.178 (1.32), 3.191 (1.13), 3.245 (0.64), 3.262 (0.62), 3.429 (1.03), 3.442 (1.40), 3.455 (0.98), 4.259 (0.75), 6.178 (0.71), 6.184 (0.82), 6.238 (0.42), 6.261 (0.41), 6.486 (1.07), 7.364 (0.49), 7.558 (0.59), 7.565 (0.57), 7.581 (0.48), 7.588 (0.49), 7.599 (0.74), 7.621 (0.71), 8.540 (0.90), 8.546 (0.92), 9.470 (0.99), 9.862 (1.03). Intermediate 19

N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phe nyl]-l -(morpholin-4-yl)cyclopropane- 1 -carboxamide

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): R _t = 1.96 min; MS (ESIpos): m/z = 513 [M+H] ⁺

Ή- MR (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 20

N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl) phenyl]-l -(4-methylpiperazin-l- yl)cyclopropane-l -carboxamide

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): R _t = 1.25 min; MS (ESIpos): m/z = 526 [M+H] ⁺ Ή- MR (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 21

4-bromo- 1 -(difluoromethoxy)-2-nitrobenzene

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-d ₆ ) δ [ppm] = 8.34 (d, 1H), 8.00 (dd, 1H), 7.56-7.18 (m, 2H)

Intermediate 22

4-(difluoromethoxy)-3-nitroaniline

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): R _t = 0.646 min; MS (ESIpos): m/z = 205.1 [M+H] ⁺

'H NMR (400MHZ, DMSO-d ₆ ) δ [ppm] = 7.23-6.83 (m, 4H), 5.79 (s, 2H)

Intermediate 23

4-bromo-2-[(tert-butoxycarbonyl)amino]benzoic acid

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.

¾ NMR (400MHz, DMSO-d ₆ ) δ [ppm] = 10.59 (s, 1H), 8.52 (d, 1H), 7.88 (d, 1H), 7.28 (dd, 1H), 1.46 (s, 9H)

Intermediate 24

tert-butyl (5-bromo-2-{[4-(difluoromethoxy)-3-nitrophenyl]carbamoyl}phe nyl)carbamate

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): R _t = 1.041 min; MS (ESIpos): m/z = 523.9 and 525.9 [M+Na] ⁺

¾ NMR (400MHz, DMSO-d ₆ ) 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 25

7-bromo-3-[4-(difluoromethoxy)-3-nitrophenyl]quinazolin-4(3H )-one

A solution of tert-butyl (5-bromo-2-((4-(difluoromethoxy)-3-nitrophenyl)carbamoyl)phe nyl)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 26

3-[3-amino-4-(difluoromethoxy)phenyl]-7-bromoquinazolin-4(3H )-one

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): R _t = 0.785 min; MS (ESIpos): m/z = 383.9 and 385.9 [M+H] ⁺

'H NMR (400MHz, DMSO-d ₆ ) 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 27

N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethox y)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide

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 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): R _t = 2.07 min; MS (ESIpos): m/z = 535 [M+H] ⁺

Ή-ΝΜΡν (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 28

N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl] - 1 -(4-methylpiperazin- 1 - yl)cyclopropane-l -carboxamide

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): R _t = 1.27 min; MS (ESIpos): m/z = 548 [M+H] ⁺

Ή- MR (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 29

2-amino-4-bromo-3-fluoro-N-(3-nitro-4-(trifluoromethoxy)phen yl)benzamide

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): t _r = 7.42 min, [M+H] ⁺ 438, 440; [M+H+CH ₃ CN] ⁺ 477, 479; [M-H] ^" 436, 438. Intermediate 30

7-bromo-8-fluoro-3-(3-nitro-4-(trifluoromethoxy)phenyl)quina zolin-

To a solution of 2-amino-4-bromo-3-fluoro-N-(3-nitro-4-(trifluoromethoxy)phen yl)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): t _r = 6.62 min, [M+H] ⁺ 448, 480; [M+H+CH ₃ CN] ⁺ 489, 491 ; [M-H] ^" 436, 438; [M-H+Cl]- 481, 483, [M-H+HCC ] ^" 491, 493.

Intermediate 11

3-(3-amino-4-(trifluoromethoxy)phenyl)-7-bromo-8-fluoroquin- azolin-4(3H)-one

To a solution of 7-bromo-8-fluoro-3-(3-nitro-4-(trifluoromethoxy)phenyl)quina zolin-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+H ₂ 0]- 434, 436; [M-H+Cl]- 452, 454; [M-H+HC02]- 462, 464.

Ή-ΝΜΡ (CDC1 ₃ ): 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 32

N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide

To a suspension of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-8-fluoroquina zolin-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): R _t = 1.18 min; MS (ESIpos): m/z = 571 [M+H] ⁺

Ή-ΝΜΡν (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 (9.11), 10.619 (8.71). Intermediate 33

4-bromo- 1 -(methoxymethyl)-2-nitrobenzene

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 34

4-(methoxymethyl)-3 -nitroaniline

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: 1 to 5: 1) to give the title compound (8.50 g, 90% purity, 52% yield) as a yellow oil.

¾ NMR (400MHz, CDC ) 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 35

tert-butyl (5-bromo-2-{[4-(methoxymethyl)-3-nitrophenyl]carbamoyl}pheny l)carbamate

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-d ₆ ) 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 36

7-bromo-3-[4-(methoxymethyl)-3-nitrophenyl]quinazolin-4(3H)- one

A solution of tert-butyl (5-bromo-2-((4-(methoxymethyl)-3-nitrophenyl)carbamoyl)pheny l)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-d ₆ ) 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 37

3 - [3 -amino -4 -(methoxymethyl)phenyl] -7 -bromoquinazolin-4(3 H) -one

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): R _t = 0.742 min; MS (ESIpos): m/z = 359.9 and 361.9 [M+H] ⁺

¾ NMR (400MHz, DMSO-d ₆ ) 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 38

-4-bromo-5-fluoro-N-[3-nitro-4-(trifluoromethoxy)phenyl]benz amide

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 aqueous 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 sil ica 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): R _t = 7.23 min, MS (ESIpos): m/z = 438 [M+H] ⁺ .

Intermediate 39

7-bromo-6-fluoro-3-[3-nitro-4-(trifluoromethoxy)phenyl]quina zolin-4-one

To a solution of 2-amino-4-bromo-5-fluoro-N-(3-nitro-4-(trifluoromethoxy)phen yl)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): R _t = 6.80 min; MS (ESIpos): m/z = 448 [M+H] ⁺ . Intermediate 40

-amino-4-(trifluoromethoxy)phenyl]-7-bromo-6-fluoro-quinazol in-

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 sodium hydrogen carbonate aqueous 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): R _t = 6.29 min, MS (ESIpos): m/z = 418 [M+H] ⁺ .

Ή-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 41

N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide

To a suspension of 3-[3-amino-4-(trifluoromethoxy)phenyl]-7-bromo-6-fluoroquina zolin-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). 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): R _t = 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 42

N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l-(4-methylpiperazin- 1 -yl)cyclopropane-l -carboxamide

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) 3-[3-amino-4- (trifluoromethoxy)phenyl]-7-bromo-6-fluoroquinazolin-4(3H)-o ne (4.00 g, 9.57 mmol) were added. This reaction mixture was stirred for 18 h at rt. Dichloromethane and water wer added subsequently and the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The crude material was purified 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): R _t = 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 43

tert-butyl(dimethyl) [(prop-2-yn- 1 -yl)oxy] silane To a solution of prop-2-yn-l-ol (11 ml, 180 mmol) and triethylamine (34 ml, 240 mmol) in dichloromethane (210 ml) was added at 0°C a solution of tert-butyl(chloro)dimethylsilane (30.9 g, 205 mmol) in dichloromethane (30 ml) and the reaction mixture was slowly warmed up to rt while stirring overnight. The reaction was diluted with water (200 ml) and the phases were separated. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with 100% cyclohexane to provide 8.59 g (28 % yield) of the title product.

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 0.086 (10.84), 0.868 (16.00), 4.281 (1.91), 4.287 (1.89). Intermediate 44

tert-butyl(dimethyl) {[(2E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2 -en-l-yl]oxy} silane

A mixture of bis(cyclopentadienyl)zirconium chloride hydride (606 mg, 2.35 mmol), 4,4,5,5- tetramethyl-l,3,2-dioxaborolane (6.9 ml, 47 mmol) and triethylamine (330 μΐ, 2.3 mmol) in THF (45 ml) was allowed to stir for 10 min at 50°C. To this mixture was then added tert-butyl(dimethyl)[(prop-2- yn-l-yl)oxy]silane (4.00 g, 23.5 mmol) and the reaction mixture was allowed to stir at 50°C overnight. After cooling to rt, the reaction was diluted with water and the THF was evaporated under reduced pressure. The resulting mixture was extracted with ethyl acetate and the organic phase was washed with brine. The organic extract was dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate to deliver 2.16 g (95 % purity, 29 % yield) of the title compound.

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 0.881 (13.82), 1.196 (16.00), 4.201 (0.72), 4.207 (0.82), 4.210 (0.83), 4.216 (0.72).

Intermediate 45

tert-butyl(dimethyl) {[trans-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclo propyl]methoxy}silane (racemate)

To a solution of tert-butyl(dimethyl) {[(2E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2 -en-l - yl]oxy} silane (2.16 g, 7.25 mmol) in dry dichloromethane (79 ml) at 0°C were added diethylzinc (1M in hexane) (14 ml, 1.0 M, 14.0 mmol) and chloro(iodo)methane (5.11 g, 29.0 mmol). The reaction mixture was allowed to stir at 0°C for 2.5 h and diluted with a saturated ammonium chloride aqueous solution. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate to deliver 1.87 g (99 % purity, 83 % yield) of the title compound.

Ή-NMR (500 MHz, CDC13) δ [ppm] : 0.871 (0.81), 0.876 (1.05), 0.882 (16.00), 1.206 (1.68), 1.211 (15.90), 2.005 (0.71).

Intermediate 46

N-[5- {7-[trans-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopro pyl]-4-oxoquinazolin-3(4H)-yl} -2- (trifluoromethoxy)phenyl] - 1 -(morpholin-4-yl)cyclopropane- 1 -carboxamide (racemate)

A suspension of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l-(morpholin- 4-yl)cyclopropane-l -carboxamide (200 mg, 361 μηιοΐ), tert-butyl(dimethyl) {[trans-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopropyl]methoxy}sila ne (169 mg, 542 μιηοΐ) and potassium carbonate (250 mg, 1.81 mmol) in a mixture of toluene (1.7 ml) and water (210 μΐ) was degassed by passing an argon stream through it for 5 min. Palladium acetate (4.06 mg, 18.1 μιηοΐ) and tricyclohexylphosphine (10.1 mg, 36.1 μιηοΐ) were then added under argon and the reaction mixture was heated to 110°C overnight. After addition of tert-butyl(dimethyl) {[trans-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclopropyl]methoxy} -silane (56.4 mg, 181 μιηοΐ), Palladium acetate (4.06 mg, 18.1 μιηοΐ) and tricyclohexylphosphine (10.1 mg, 36.1 μιηοΐ), the reaction mixture was allowed to stir overnight at 110°C. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was purified by preparative RP-HPLC (125x40mm) with acetonitrile/water (0.1% formic acid) followed by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate to deliver 69.5 mg (95 % purity, 28 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.54 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (0.83), 0.056 (10.68), 0.870 (16.00), 1.078 (0.48), 1.092 (0.54), 1.113 (0.55), 1.120 (0.96), 1.128 (1.03), 1.138 (0.52), 1.146 (0.88), 1.264 (0.43), 1.274 (0.98), 1.282 (0.82), 2.463 (1.38), 2.474 (1.06), 3.618 (0.44), 3.701 (1.35), 3.722 (0.56), 3.736 (0.47), 7.292 (0.44), 7.296 (0.46), 7.313 (0.45), 7.317 (0.48), 7.381 (0.44), 7.388 (0.43), 7.403 (0.50), 7.410 (0.58), 7.417 (0.93), 7.420 (0.89), 7.677 (0.41), 8.041 (0.79), 8.061 (0.73), 8.318 (1.71), 8.521 (0.82), 8.528 (0.81), 10.610 (0.90). Intermediate 47

1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropanecarbonitrile

To a solution of 6-oxa-3-azabicyclo[3.1.1]heptane TsOH salt (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- MR (400 MHz, MeOD) δ [ppm] : 1.15 - 1.17 (m, 2H) 1.24 - 1.26 (m, 2H), 2.11 (d, 1H), 2.98 - 3.00 (m, 1H), 3.07 - 3.15 (m, 4H), 4.53 (d, 2H).

Intermediate 48

1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane-l -carboxamide

To a solution of l -(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropanecarbonitr ile (5.00 g, 30.5 mmol) and potassium carbonate (4.20 g, 30.5 mmol) in DMSO (50 ml) was added hydrogen peroxide (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): R _t = 0.39 min; MS (ESIpos): m/z = 183 [M+H] ⁺ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 0.95 - 0.98 (m, 2H) 1.09 - 1.62 (m, 2H), 2.10 (d, 1H), 2.88 - 2.95 (m, 2H), 3.03 (d, 2H), 4.48 (d, 1H), 7.00 (s, 1H), 7.62 (s, 1H).

Intermediate 49

N-[5-nitro-2-(trifluoromethoxy)phenyl] - 1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane- 1 - carboxamide

A mixture of 2-bromo-4-nitro-l -(trifluoromethoxy)benzene (518 mg, 1.81 mmol), l-(6-oxa-3- azabicyclo [3. l .l]heptan-3-yl)cyclopropane-l -carboxamide (300 mg, 1.65 mmol), tris(dibenzylidenacetone)dipalladium (151 mg, 165 μιηοΐ), Xantphos (191 mg, 329 μιηοΐ) and cesium carbonate (1.61 g, 4.94 mmol) was suspended in 1,4-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): R _t = 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 50

N-[5-amino-2-(trifluoromethoxy)phenyl] - 1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane- 1 - carboxamide

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). Pd/C 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): R _t = 0.84 min; MS (ESIpos): m/z = 358 [M+H] ⁺

Ή- MR (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 51

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

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 EtOAc. After phase separation, the aqueous layer was extracted with EtOAc. 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/EtOAc from 93:7 to 40:60 to provide 318 mg (99 % purity, 82 % yield) of the title compound.

LC-MS (Method 6): R _t = 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 52

2-amino-4-bromo-N-[3- {[1 -(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-yl)cyclopropane-l -carbonyl] amino} -4- (trifluoromethoxy)phenyl]benzamide

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 the catalyst (CAS 7440-06-4) platinum 1% and vanadium 2% over active charcoal (32.8 mg) 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): R _t = 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 53

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

2-amino-4-bromo-N-[3- {[l-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cyclopropane-l-car bonyl]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): R _t = 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). Working examples:

Example 1

tert-Butyl 4- {3-[3-( {[l-(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoro methoxy)phenyl]-4- oxo-3,4-dihydroquinazolin-7-yl}piperazine-l-carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (20.0 mg, 36.1 μmol), tert-butyl piperazine-l-carboxylate (12.1 mg, 65.1 μιηοΐ), tris(dibenzylidenacetone)dipalladium (3.31 mg, 3.61 μmol), Di-t-butyl(2,2-diphenyl-l -methyl- 1 - cyclopropyl)phosphine (2.55 mg, 7.23 μιηοΐ) and cesium carbonate (35.3 mg, 108 μιηοΐ) was suspended in dioxane (360 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 95°C for 16 h. After cooling to rt, 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 purified by RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to deliver 10.5 mg (98 % purity, 43 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.18 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.62), 1.121 (1.00), 1.128 (1.10), 1.138 (0.52), 1.234 (0.42), 1.264 (0.55), 1.275 (1.24), 1.281 (0.99), 1.293 (0.46), 1.433 (16.00), 2.463 (1.58), 3.421 (1.47), 3.435 (1.46), 3.479 (1.38), 3.494 (1.40), 3.700 (1.60), 7.020 (0.83), 7.025 (0.90), 7.226 (0.43), 7.232 (0.43), 7.249 (0.45), 7.255 (0.44), 7.358 (0.48), 7.365 (0.49), 7.380 (0.56), 7.387 (0.59), 7.658 (0.50), 7.680 (0.41), 7.969 (0.98), 7.992 (0.88), 8.246 (2.01), 8.494 (0.94), 8.500 (0.99), 10.604 (1.05).

Example 2

tert-Butyl 4- {3-[3-{[2-(morpholin-4-yl)propanoyl]amino} -4-(trifluoromethoxy)phenyl]-4- dihydroquinazolin-7-yl}piperazine-l-carboxylate (racemate)

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-2-(morpholin-4- yl)propanamide (racemate) (280 mg, 502 μιηοΐ), tert-butyl piperazine-l -carboxylate (168 mg, 903 μιηοΐ), tris(dibenzylidenaceton)dipalladium (45.9 mg, 50.2 μιηοΐ), Di-t-butyl(2,2-diphenyl-l -methyl- 1- cyclopropyl)phosphine (35.4 mg, 100 μιηοΐ) and cesium carbonate (490 mg, 1.51 mmol) in dioxane (5.0 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 95°C for 18 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 purified by RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to deliver 180 mg (93 % purity, 52 % yield) of the desired compound.

LC-MS (Method 1): R _t = 0.99 min; MS (ESIpos): m/z = 647 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 0.008 (0.42), 1.189 (2.28), 1.207 (2.22), 1.244 (0.54), 1.261 (0.48), 1.276 (0.58), 1.292 (0.47), 1.435 (16.00), 3.389 (0.66), 3.407 (0.88), 3.423 (1.39), 3.430 (1.19), 3.438 (1.26), 3.482 (1.16), 3.496 (1.16), 3.641 (0.91), 3.651 (1.60), 3.662 (0.91), 7.024 (0.76), 7.030 (0.80), 7.253 (0.40), 7.376 (0.48), 7.383 (0.48), 7.398 (0.67), 7.405 (0.63), 7.627 (0.43), 7.630 (0.45), 7.976 (0.93), 7.998 (0.83), 8.252 (2.07), 8.344 (0.87), 8.351 (0.86), 10.070 (0.91).

Example 3

tert-Butyl 4- {3-[3-( {[l-(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoro methoxy)phenyl]-4- oxo-3,4-dihydroquinazolin-7-yl}piperidine-l-carboxylate

l-(Morpholin-4-yl)cyclopropanecarboxylic acid hydrochloride (1 : 1) (28.4 mg, 137 μηιοΐ) was suspended in dichloromethane (4.6 ml) and l -chloro-N,N,2-trimethylprop-l -en- 1 -amine (75 μΐ, 96% purity, 550 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 (4.6 ml) and the mixture was once more evaporated. The residue was then suspended in dichloromethane (4.6 ml) and pyridine (33 μΐ, 410 μιηοΐ) and tert-butyl 4- {3-[3-amino-4-(trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroqui nazolin-7-yl}piperidine- 1 -carboxylate (69.0 mg, 100% purity, 137 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 27.0 mg (30 % yield) of the title product.

LC-MS (Method 6): R _t = 2.43 min; MS (ESIpos): m/z = 658 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.91), 0.008 (0.85), 1.122 (0.94), 1.129 (1.02), 1.139 (0.48), 1.234 (0.75), 1.265 (0.52), 1.275 (1.06), 1.283 (0.90), 1.429 (16.00), 1.595 (0.44), 1.826 (0.53), 1.856 (0.42), 2.465 (1.51), 3.701 (1.45), 7.376 (0.51), 7.383 (0.51), 7.398 (0.57), 7.405 (0.57), 7.522 (0.52), 7.543 (0.55), 7.588 (1.02), 7.683 (0.47), 7.702 (0.40), 8.111 (0.93), 8.132 (0.84), 8.341 (2.05), 8.528 (1.00), 8.535 (1.02), 10.615 (0.96).

Example 4

tert-Butyl 4- {3-[3-( {[l-(4-methylpiperazin-l-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l-(4- methylpiperazin-l -yl)cyclopropanecarboxamide (150 mg, 265 μιηοΐ), tert-butyl piperazine-1 - carboxylate (88.8 mg, 477 μιηοΐ), tris(dibenzylidenaceton)dipalladium (24.3 mg, 26.5 μιηοΐ), Di-t- butyl(2,2-diphenyl-l-methyl-l -cyclopropyl)phosphine (18.7 mg, 53.0 μmol) and cesium carbonate (259 mg, 795 μιηοΐ) in dioxane (2.6 ml) was degassed by passing argon through it for 5 min and then the mixture was heated at 95°C for 18 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 purified by RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to deliver 45.0 mg (94 % purity, 24 % yield) of the title compound.

LC-MS (Method 1): R _t = 0.77 min; MS (ESIpos): m/z = 672 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.75), 0.008 (0.65), 1.113 (0.87), 1.120 (0.96), 1.130 (0.46), 1.233 (0.50), 1.243 (1.43), 1.250 (0.85), 1.261 (0.69), 1.276 (0.54), 1.291 (0.45), 1.433 (16.00), 2.192 (3.84), 3.420 (1.28), 3.427 (1.19), 3.434 (1.26), 3.479 (1.20), 3.493 (1.19), 7.018 (0.78), 7.024 (0.82), 7.226 (0.40), 7.248 (0.42), 7.255 (0.40), 7.344 (0.51), 7.351 (0.51), 7.366 (0.55), 7.373 (0.58), 7.649 (0.42), 7.653 (0.43), 7.968 (0.96), 7.991 (0.87), 8.246 (2.12), 8.545 (0.97), 8.551 (0.98), 10.640 (0.93).

Example 5

tert-Butyl 4- {3-[3-{[2-(4-methylpiperazin-l -yl)propanoyl]amino} -4-(trifluoromethoxy)phenyl]-4- 3 ,4-dihydroquinazolin-7-yl} piperazine- 1 -carboxylate (enantiomer 1 )

Enantiomer separation of 130 mg of tert-butyl 4- {3-[3-{[2-(4-methylpiperazin-l-yl)propanoyl]amino}- 4-(trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl }piperazine-l-carboxylate (racemate) (94% purity) gave 51 mg of enantiomer 2 (chiral HPLC: Rt = 10.50 min) and 58 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 9.76 min; 99% ee.

Separating method: column: Daicel Chiralcel OX-H 5 μιη, 250 mm x 20mm; mobile phase: ethanol 100%) with 0.2%) diethylamine; temperature: 60°C; flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 4.6 mm; mobile phase: ethanol 100%) with 0.2%) diethylamine; flow rate: 1 ml/min; temperature: 60°C; UV detection: 235 nm.

LC-MS (Method 1): R _t = 0.78 min; MS (ESIpos): m/z = 660 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.07), 0.008 (1.05), 1.173 (2.13), 1.191 (2.17), 1.434 (16.00), 2.177 (4.05), 2.523 (0.70), 3.408 (0.98), 3.425 (1.78), 3.438 (1.30), 3.482 (1.19), 3.496 (1.19), 7.024 (0.77), 7.029 (0.83), 7.253 (0.41), 7.259 (0.41), 7.357 (0.52), 7.363 (0.51), 7.379 (0.58), 7.385 (0.60), 7.626 (0.44), 7.629 (0.48), 7.975 (1.00), 7.998 (0.88), 8.253 (2.26), 8.427 (0.97), 8.434 (0.98), 10.129 (0.92).

Example 6

tert-Butyl 4- {3-[3-{[2-(morpholin-4-yl)propanoyl]amino} -4-(trifluoromethoxy)phenyl]-4-oxo-3,4- dihydroquinazolin-7-yl}piperazine-l-carboxylate (enantiomer 1)

Enantiomer separation of 180 mg of tert-butyl 4- {3-[3- {[2-(morpholin-4-yl)propanoyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate (racemate) (93% purity) gave 70 mg of enantiomer 2 (chiral HPLC: Rt = 11.67 min) and 70 mg of the title compound (enantiomer 1): chiral HPLC: Rt = 10.90 min; 99% ee.

Two consecutive chiral separations were performed, the second one with the mixed fractions from the first one.

First separating method: column: Daicel Chiralcel OX-H, 5 μιη, 250 mm x 20mm; mobile phase: ethanol 100%) with 0.2% diethylamine; temperature: 60°C; flow rate: 15 ml/min; UV detection: 220 nm.

Second separating method: column: YMC Chiralart Cellulose SB, 5 μιη, 250 mm x 20mm; mobile phase: n-heptane 50%>/ethanol 50%> with 0.2%> diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralcel OX-H 5 μιη, 250 mm x 4.6 mm; mobile phase: ethanol 100%) with 0.2%) diethylamine; flow rate: 1 ml/min; temperature: 60°C; UV detection: 235 nm.

LC-MS (Method 1): R _t = 0.99 min; MS (ESIpos): m/z = 647 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.67), 0.008 (0.60), 1.189 (2.21), 1.207 (2.25), 1.434 (16.00), 2.523 (0.52), 2.557 (1.08), 2.569 (0.60), 3.389 (0.67), 3.406 (0.89), 3.423 (1.42), 3.430 (1.21), 3.437 (1.26), 3.482 (1.19), 3.496 (1.20), 3.640 (0.89), 3.651 (1.58), 3.662 (0.90), 7.024 (0.78), 7.029 (0.82), 7.252 (0.42), 7.258 (0.40), 7.376 (0.52), 7.383 (0.51), 7.398 (0.57), 7.404 (0.59), 7.626 (0.45), 7.630 (0.48), 7.648 (0.41), 7.975 (0.98), 7.998 (0.88), 8.251 (2.25), 8.344 (0.94), 8.351 (0.95), 10.070 (0.95).

Example 7

tert-Butyl 4- {3-[3-( {[l-(4-methylpiperazin-l-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3-oxopiperazine-l -carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l-(4- methylpiperazin-l -yl)cyclopropanecarboxamide (50.0 mg, 88.3 μιηοΐ), tert-butyl 3-oxopiperazine-l - carboxylate (CAS 76003-29-7) (36.1 mg, 98% purity, 177 μιηοΐ), copper(I) iodide (3.36 mg, 17.7 μιηοΐ), Ν,Ν'-dimethylethylendiamine (1.9 μΐ, 18 μmol) and cesium carbonate (57.5 mg, 177 μιηοΐ) under argon in dry 1,4-dioxane (880 μΐ) was degassed by passing an argon stream through it for 5 min. The vial was then sealed and the reaction mixture was heated to 120°C for 18 h. After cooling down to rt, the reaction mixture was directly purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to provide 11.3 mg (19 % yield) of the title product.

LC-MS (Method 6): R _t = 1.28 min; MS (ESIpos): m/z = 686 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.117 (0.98), 1.125 (1.08), 1.135 (0.54), 1.237 (0.57), 1.247 (1.10), 1.254 (0.92), 1.389 (0.42), 1.456 (16.00), 2.194 (3.95), 3.709 (0.46), 3.721 (0.81), 3.734 (0.60), 3.882 (0.75), 3.897 (0.97), 3.909 (0.57), 4.146 (1.16), 7.384 (0.46), 7.390 (0.47), 7.406 (0.52), 7.412 (0.54), 7.636 (0.49), 7.642 (0.53), 7.658 (0.52), 7.663 (0.59), 7.686 (0.48), 7.705 (0.41), 7.750 (1.02), 7.755 (0.98), 8.173 (0.96), 8.195 (0.85), 8.375 (1.83), 8.599 (0.90), 8.606 (0.92), 10.655 (0.97).

Example 8

Methyl 4-{3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromet hoxy)phenyl]-4- 3,4-dihydroquinazolin-7-yl}piperazine-l-carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (50.0 mg, 98%> purity, 88.6 μιηοΐ), methyl piperazine-l -carboxylate (23.0 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C for 16 h.

After cooling to rt, 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 purified by RP-HPLC

125x30mm with acetonitrile/water (0.2%> ammonia) to deliver 25.6 mg (98 % purity, 46 % yield) of the title compound. LC-MS (Method 6): R _t = 1.95 min; MS (ESIpos): m/z = 617 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.20), 0.008 (2.59), 1.108 (0.98), 1.120 (2.76), 1.128 (3.02), 1.138 (1.39), 1.264 (1.28), 1.274 (2.93), 1.281 (2.55), 1.294 (1.01), 2.328 (0.45), 2.463 (4.35), 2.670 (0.49), 3.435 (2.34), 3.446 (4.19), 3.453 (3.72), 3.460 (4.22), 3.527 (4.09), 3.534 (3.63), 3.541 (4.20), 3.552 (2.44), 3.642 (16.00), 3.700 (4.32), 7.023 (2.36), 7.029 (2.59), 7.231 (1.23), 7.237 (1.18), 7.253 (1.27), 7.259 (1.26), 7.358 (1.27), 7.365 (1.31), 7.380 (1.43), 7.387 (1.51), 7.658 (1.25), 7.677 (1.08), 7.972 (2.87), 7.995 (2.59), 8.247 (5.09), 8.494 (2.48), 8.500 (2.53), 10.603 (2.88).

Example 9

N-{5-[7-(4-Methoxypiperidin-l-yl)-4-oxoquinazolin-3(4H)-yl]- 2-(trifluoromethoxy)phenyl} -l - (morpholin-4-yl)cyclopropanecarboxamide

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (50.0 mg, 98% purity, 88.6 μιηοΐ), 4-methoxypiperidine (18.4 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C for 16 h. After cooling to rt, the reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol 100:0 to 85: 15. The material obtained was then purified by RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 18.6 mg (36 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.08 min; MS (ESIpos): m/z = 588 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.19), 0.008 (1.33), 1.110 (0.78), 1.122 (2.22), 1.130 (2.48), 1.140 (1.15), 1.264 (1.04), 1.274 (2.41), 1.281 (2.07), 1.293 (0.82), 1.486 (0.63), 1.495 (0.98), 1.506 (0.74), 1.518 (1.02), 1.526 (0.73), 1.540 (0.44), 1.922 (0.84), 1.937 (0.75), 1.953 (0.73), 2.463 (3.35), 2.473 (2.56), 3.166 (0.66), 3.173 (0.75), 3.189 (0.76), 3.198 (1.33), 3.206 (0.85), 3.222 (0.81), 3.230 (0.72), 3.286 (16.00), 3.430 (0.44), 3.441 (0.62), 3.451 (0.83), 3.460 (0.66), 3.471 (0.42), 3.700 (3.38), 3.725 (0.88), 3.737 (1.05), 3.751 (0.79), 3.772 (0.88), 3.782 (0.59), 7.002 (1.84), 7.008 (1.96), 7.226 (0.93), 7.232 (0.91), 7.248 (0.99), 7.255 (0.97), 7.350 (1.14), 7.357 (1.14), 7.372 (1.25), 7.379 (1.32), 7.652 (0.97), 7.655 (1.03), 7.674 (0.90), 7.677 (0.88), 7.936 (2.21), 7.959 (2.02), 8.221 (4.52), 8.489 (2.12), 8.496 (2.15), 10.602 (2.26).

Example 10

l-(4-Methylpiperazin-l-yl)-N-{5-[4-oxo-7-(tetrahydro-2H-p yran-4-yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl}cyclopropanecarboxamide

4,4'-Di-tert-butyl-2,2'-bipyridine (8.05 mg, 0.03 mmol) and 1,2-dimethoxyethane- dichloronickel (1 : 1) (5.49 mg, 0.025 mmol) were charged under argon in a flask and suspended in dry 1,2-dimethoxyethane (2 ml). This mixture was sonicated for 5 min. In a separated microwave vial under argon Iridium(l+), [4,4'-bis( 1 , 1 -dimethylethyl)-2,2'-bipyri

pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (5.61 mg, 5.00 μιηοΐ), N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l-(4- methylpiperazin-l -yl)cyclopropanecarboxamide (56.6 mg, 100 μιηοΐ), and lithium hydroxide (4.79 mg, 200 μιηοΐ) were dissolved in 1,2-dimethoxyethane (0.6 ml) and 4-bromotetrahydro-2H-pyran (17 μΐ, 150 μιηοΐ) and 1,1,1, 3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (31 μΐ, 100 μιηοΐ) were added under argon. 0.4 ml of the solution of the first flask (catalyst mix) was added to the microwave vial mixture and an argon stream was passed through the resulting mixture for 10 min. The reaction mixture was irradiated with one 34 W blue LED lamp in the EvoluChem™ Photochemistry Device using the 8 x 2 mL vial rack which contains an incorportated fan for cooling to maintain experiment at room temperature. The reaction mixture was then allowed to stir in the device for 15 hours. The reaction mixture was then charged completely on a silica gel column and a chromatographic separation was performed with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was then purified by preparative RP-HPLC on a 125x30mm with acetonitrile/water (0.2% ammonia) to obtain 25.5 mg (97 % purity, 43 % yield) of the title product.

LC-MS (Method 6): R _t = 1.18 min; MS (ESIpos): m/z = 572 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.71), 0.008 (2.39), 1.102 (1.40), 1.115 (3.81), 1.123 (4.40), 1.132 (2.09), 1.235 (2.04), 1.245 (4.39), 1.252 (3.56), 1.265 (1.45), 1.714 (0.41), 1.736 (1.31), 1.747 (1.12), 1.764 (3.86), 1.774 (5.09), 1.787 (3.43), 1.795 (3.34), 2.157 (0.78), 2.195 (16.00), 2.328 (0.72), 2.332 (0.60), 2.366 (0.69), 2.454 (6.05), 2.670 (0.59), 2.980 (0.65), 2.992 (0.73), 3.004 (1.08), 3.018 (0.76), 3.030 (0.50), 3.449 (1.27), 3.460 (1.13), 3.477 (2.36), 3.485 (2.44), 3.504 (1.21), 3.512 (1.41), 3.972 (2.94), 3.979 (2.01), 3.998 (2.13), 7.366 (2.14), 7.372 (2.14), 7.388 (2.37), 7.394 (2.50), 7.531 (2.02), 7.535 (2.22), 7.552 (2.12), 7.555 (2.45), 7.597 (4.28), 7.675 (1.83), 7.679 (1.89), 7.697 (1.67), 7.701 (1.58), 8.122 (3.87), 8.142 (3.56), 8.346 (8.33), 8.356 (0.44), 8.582 (3.80), 8.588 (3.82), 10.651 (3.83).

Example 11

N-[5-(7-Cyclobutyl-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromet hoxy)phenyl] - 1 -(4-methylpiperazin- 1 - yl)cyclopropanecarboxamide

Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl,KNl ']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (5.61 mg, 5.00 μιηοΐ), N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l -(4-methylpiperazin- 1 -yl)cyclopropanecarboxamide (56.6 mg, 100 μιηοΐ), and lithium hydroxide (4.79 mg, 200 μιηοΐ) were loaded in a 2 ml vial. The nickel pre -catalyst was then prepared in a second microwave vial. To this vial, nickel (II) chloride dimethoxyethane adduct (10.99 mg, 0.05 mmol, 0.5 equiv.) and 4,4'-di-tert-butyl-2,2'-bipyridine (16.10 mg, 0.06 mmol, 0.6 equiv.) were loaded and dissolved in 10 mL of 1,2-dimethoxyethane, placed under argon, sealed and sonicated for 5 minutes. 1 mL of the nickel pre -catalyst solution was syringed into the vial containing the reaction mixture. The solution was degassed a second time by sparging with argon while stirring for 10 minutes. Under a constant flow of argon, bromocyclobutane (14 μΐ, 150 μιηοΐ) and 1,1,1,3,3,3- hexamethyl-2-(trimethylsilyl)trisilane (31 μΐ, 100 μιηοΐ) were then added to the reaction mixture using a Hamilton syringe. The cap of the microwave vial was then removed and replaced with a new cap. The reaction mixture was irradiated with one 34 W blue LED lamp in the EvoluChem™ Photochemistry Device using the 8 x 2 mL vial rack which contains an incorporated fan for cooling to maintain experiment at room temperature. The reaction mixture was allowed to stir in the device for 15 hours. The reaction mixture was charged completely on a silica gel column and a chromatographic separation was performed with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was purified by preparative RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to provide 15.0 mg (27 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.46 min; MS (ESIneg): m/z = 540 [M-H] ^"

Ή-ΝΜΡν (400 MHz, DMSO-d6) δ [ppm] : -0.149 (1.78), -0.008 (16.00), 0.008 (13.16), 0.146 (1.62), 0.969 (2.12), 1.131 (5.30), 1.239 (6.30), 1.861 (1.51), 1.884 (2.01), 2.004 (1.23), 2.028 (2.17), 2.053 (2.51), 2.078 (1.67), 2.160 (3.07), 2.167 (3.18), 2.189 (4.35), 2.213 (3.46), 2.327 (4.24), 2.358 (2.68), 2.379 (4.96), 2.400 (4.79), 2.669 (3.57), 2.709 (1.56), 3.708 (1.90), 3.730 (2.45), 3.751 (1.62), 7.394 (2.17), 7.410 (2.12), 7.479 (3.40), 7.500 (3.79), 7.546 (6.47), 7.675 (2.95), 7.693 (2.90), 8.114 (6.63), 8.134 (5.91), 8.342 (14.77).

Example 12

l-(4-Methylpiperazin-l-yl)-N-[5- {4-oxo-7-(tetrahydrofuran-3-yl)quinazolin-3(4H)-yl} -2- (trifluoromethoxy)phenyl] cyclopropanecarboxamide (racemate)

4,4'-Di-tert-butyl-2,2'-bipyridine (16.10 mg, 0.06 mmol, 0.6 equiv.) and 1 ,2-dimethoxyethane - dichloronickel (1 : 1) (10.99 mg, 0.05 mmol, 0.5 equiv.) were charged under argon in a flask and suspended in dry 1 ,2-dimethoxyethane (10 ml). This mixture was sonicated for 5 min. In a separated microwave vial under argon Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl ,KN ]bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l -) (1 : 1) (CAS 870987-63-6) (5.61 mg, 5.00 μιηοΐ), N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(4-methylpiperazin-l-yl)cyclopro panecarboxamide (56.6 mg, 100 μιηοΐ), and lithium hydroxide (4.79 mg, 200 μιηοΐ) were charged in a 2 mL vial. 1 mL of the nickel pre-catalyst solution was syringed into the vial containing the reaction mixture. The solution was degassed a second time by sparging with argon while stirring for 10 minutes. Under a constant flow of argon, 3- bromotetrahydrofurane (racemate) (14 μΐ, 150 μιηοΐ) and l,l,l,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (31 μΐ, 100 μιηοΐ) were added to the reaction mixture using a Hamilton syringe. The reaction mixture was irradiated with one 34 W blue LED lamp in the EvoluChem™ Photochemistry Device using the 8 x 2 mL vial rack which contains an incorporated fan for cooling to maintain the experiment at room temperature. The reaction mixture was then allowed to stir in the device for 15 hours. The reaction mixture was charged completely on a silica gel column and a chromatographic separation was performed with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was purified by preparative RP-HPLC on a 125x30mm column with acetonitrile/water (0.2% ammonia) to provide 10.0 mg (96 % purity, 17 % yield) of the title compound.

LC-MS (Method 2): R _t = 1.88 min; MS (ESIpos): m/z = 558 [M+H] ⁺

Ή-ΝΜΡν (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.09), 0.007 (0.77), 1.106 (1.50), 1.115 (4.03), 1.122 (4.31), 1.129 (1.98), 1.237 (1.98), 1.245 (4.44), 1.251 (3.60), 1.261 (1.50), 1.908 (0.53), 1.968 (0.47), 1.983 (1.12), 1.992 (0.62), 1.999 (1.14), 2.008 (1.32), 2.014 (0.54), 2.024 (1.29), 2.039 (0.54), 2.194 (16.00), 2.359 (0.43), 2.362 (0.50), 2.366 (0.46), 2.375 (0.89), 2.384 (1.03), 2.391 (1.41), 2.400 (1.97), 2.406 (1.52), 2.409 (1.46), 2.415 (2.29), 2.425 (2.09), 2.431 (2.27), 2.453 (4.01), 2.519 (0.66), 2.523 (0.54), 3.249 (1.47), 3.265 (1.68), 3.286 (1.08), 3.577 (0.40), 3.592 (1.13), 3.607 (1.72), 3.622 (1.37), 3.636 (0.55), 3.651 (2.79), 3.667 (2.88), 3.681 (1.82), 3.813 (1.07), 3.828 (2.52), 3.844 (2.88), 3.859 (1.21), 3.981 (1.12), 3.990 (1.19), 3.997 (2.06), 4.007 (2.02), 4.014 (0.95), 4.023 (0.88), 4.079 (2.08), 4.094 (2.64), 4.095 (2.57), 4.110 (1.82), 7.374 (2.49), 7.379 (2.51), 7.391 (2.59), 7.396 (2.80), 7.528 (2.04), 7.531 (2.08), 7.545 (2.10), 7.548 (2.20), 7.629 (3.95), 7.633 (3.60), 7.677 (1.95), 7.680 (1.86), 7.691 (0.78), 7.694 (1.63), 7.697 (1.50), 8.127 (4.08), 8.143 (3.73), 8.352 (9.84), 8.365 (0.76), 8.584 (4.25), 8.589 (4.19), 10.650 (3.53).

Example 13

tert-Butyl (l- {3-[3-( {[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4-(trifluoromet hoxy)phenyl]-4- oxo-3,4-dihydroquinazolin-7-yl}azetidin-3-yl)carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (50.0 mg, 98% purity, 88.6 μιηοΐ), tert-butyl azetidin-3-ylcarbamate (28.0 mg, 98% purity, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in dioxane (880 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C for 16 h. After cooling to rt, 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 purified by preparative RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to deliver 17.3 mg (94 % purity, 28 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.11 min; MS (ESIpos): m/z = 645 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.120 (0.95), 1.127 (1.01), 1.137 (0.46), 1.263 (0.47), 1.273 (1.04), 1.280 (0.87), 1.354 (0.58), 1.378 (0.52), 1.402 (16.00), 2.462 (1.44), 2.472 (1.11), 3.699 (1.40), 3.781 (0.56), 3.796 (0.69), 3.801 (0.70), 3.816 (0.62), 4.235 (0.44), 4.255 (0.93), 4.275 (0.48), 6.480 (0.86), 6.485 (0.92), 6.647 (0.45), 6.652 (0.42), 6.669 (0.47), 6.674 (0.45), 7.348 (0.52), 7.354 (0.52), 7.370 (0.58), 7.376 (0.61), 7.647 (0.50), 7.651 (0.51), 7.669 (0.41), 7.939 (1.03), 7.961 (0.96), 8.216 (2.15), 8.482 (1.02), 8.488 (1.04), 10.600 (0.99).

Example 14

N-[5-(7-Cyclopentyl-4-oxoquinazolin-3(4H)-yl)-2-(trifluorome thoxy)phenyl]-l -(4-methylpipe] yl)cyclopropanecarboxamide

In a 2 mL vial, Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl ,KNl']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (5.61 mg, 5.00 μηιοΐ), N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(4-methylpiperazin-l-yl)cyclopro panecarboxamide (56.6 mg, 100 μιηοΐ), and lithium hydroxide (4.79 mg, 200 μιηοΐ) were loaded. The nickel pre -catalyst was then prepared in a second microwave vial. To this vial, nickel (II) chloride dimethoxyethane adduct (10.99 mg, 0.05 mmol, 0.5 equiv.) and 4,4'-di-tert-butyl-2,2'-bipyridine (16.10 mg, 0.06 mmol, 0.6 equiv.) were loaded and dissolved in 10 mL of 1 ,2-dimethoxyethane, placed under argon, sealed and sonicated for 5 minutes. 1 mL of the nickel pre -catalyst solution was syringed into the vial containing the reaction mixture. The solution was degassed a second time by sparging with argon while stirring for 10 minutes. Under a constant flow of argon, bromocyclopentane (16 μΐ, 150 μιηοΐ) and l,l,l,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane (31 μΐ, 100 μιηοΐ) were added to the reaction mixture using a Hamilton syringe. The reaction mixture was irradiated with one 34 W blue LED lamp in the EvoluChem™ Photochemistry Device using the 8 x 2 mL vial rack which contains an incorportated fan for cooling to maintain experiment at room temperature. The reaction mixture was allowed to stir in the device for 15 hours. The reaction mixture was then charged completely on a silica gel column and a chromatographic separation was performed with a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was purified by preparative RP-HPLC on a 125x30mm column with acetonitrile/water (0.2% ammonia) to provide 11 mg (20% yield) of the title compound.

LC-MS (Method 1): R _t = 0.81 min; MS (ESIneg): m/z = 554 [M-H] ^"

Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : -0.007 (0.51), 1.106 (1.48), 1.115 (3.91), 1.122 (4.15), 1.129 (1.91), 1.236 (1.93), 1.244 (4.28), 1.250 (3.47), 1.260 (1.44), 1.605 (0.97), 1.612 (0.89), 1.617 (1.01), 1.624 (1.38), 1.628 (1.40), 1.636 (1.11), 1.641 (1.26), 1.646 (1.15), 1.655 (0.78), 1.662 (0.98), 1.675 (0.96), 1.682 (1.10), 1.685 (1.02), 1.691 (1.94), 1.701 (1.71), 1.705 (1.60), 1.715 (1.17), 1.731 (0.42), 1.795 (0.67), 1.798 (0.68), 1.806 (1.27), 1.808 (1.28), 1.813 (1.39), 1.819 (2.13), 1.823 (2.01), 1.828 (1.28), 1.835 (0.90), 2.078 (0.69), 2.094 (1.27), 2.101 (1.41), 2.104 (1.48), 2.111 (1.38), 2.113 (1.33), 2.116 (1.33), 2.132 (0.70), 2.193 (16.00), 2.359 (0.41), 2.363 (0.47), 2.366 (0.44), 2.523 (0.52), 3.168 (0.87), 3.186 (1.41), 3.202 (0.85), 7.369 (2.46), 7.374 (2.37), 7.387 (2.55), 7.392 (2.57), 7.508 (2.04), 7.512 (2.10), 7.525 (2.10), 7.528 (2.21), 7.581 (4.01), 7.584 (3.59), 7.674 (1.80), 7.677 (1.78), 7.691 (1.65), 7.694 (1.48), 8.098 (4.06), 8.115 (3.70), 8.333 (9.55), 8.581 (4.46), 8.586 (4.35), 10.650 (3.58).

Example 15

N-{5-[7-(4-Hydroxy-4-methylpiperidin-l-yl)-4-oxoquinazolin-3 (4H)-yl]-2-(trifluorometho

1 -(4-methylpiperazin- 1 -yl)cyclopropanecarboxamide

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l-(4- methylpiperazin-l -yl)cyclopropanecarboxamide (50.0 mg, 88.3 μηιοΐ), 4-methylpiperidin-4-ol (15.3 mg, 132 μηιοΐ), tris(dibenzylidenacetone)dipalladium (4.04 mg, 4.41 μηιοΐ), Xantphos (6.13 mg, 10.6 μηιοΐ) and cesium carbonate (40.3 mg, 124 μηιοΐ) was suspended in dioxane (880 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C for 16 h. After cooling to rt, 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 purified by RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to deliver 12.7 mg (24 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.12 min; MS (ESIneg): m/z = 599 [M-H] ^"

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.35), 0.008 (2.13), 1.102 (1.13), 1.115 (3.17), 1.122 (3.59), 1.132 (1.78), 1.159 (16.00), 1.233 (1.63), 1.242 (3.54), 1.250 (2.93), 1.262 (1.21), 1.508 (0.45), 1.531 (1.73), 1.557 (4.82), 1.590 (0.55), 2.192 (13.66), 2.328 (0.77), 2.366 (0.67), 2.450 (4.97), 2.670 (0.71), 3.349 (1.91), 3.360 (1.30), 3.372 (1.09), 3.383 (1.05), 3.631 (1.95), 3.664 (1.60), 3.741 (0.49), 4.407 (4.20), 6.981 (2.76), 6.987 (2.87), 7.210 (1.38), 7.216 (1.36), 7.233 (1.47), 7.239 (1.43), 7.331 (1.79), 7.338 (1.75), 7.353 (1.94), 7.360 (2.01), 7.644 (1.53), 7.648 (1.62), 7.666 (1.39), 7.921 (3.40), 7.944 (3.06), 8.210 (7.31), 8.538 (3.46), 8.544 (3.42), 10.638 (3.32).

Example 16

N-[5- {7-[3-Hydroxypiperidin-l-yl]-4-oxoquinazolin-3(4H)-yl} -2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropanecarboxamide (racemate)

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (50.0 mg, 98% purity, 88.6 μιηοΐ), piperidin-3-ol (racemate) (16.1 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (10.2 mg, 17.7 μιηοΐ), Xantphos (86.6 mg, 266 μιηοΐ) and cesium carbonate (8.11 mg, 8.86 μιηοΐ) was suspended in dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C for 16 h. After cooling to rt, 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 purified by preparative RP-HPLC (125x30mm) with acetonitrile/water (0.2% ammonia) to deliver 3.50 mg (100 % purity, 7 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.78 min; MS (ESIpos): m/z = 574 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (4.19), 0.008 (4.39), 0.146 (0.54), 1.110 (2.53), 1.122 (7.16), 1.130 (7.91), 1.140 (3.70), 1.264 (3.41), 1.274 (7.86), 1.281 (6.62), 1.294 (2.74), 1.371 (0.47), 1.381 (0.54), 1.402 (1.24), 1.409 (1.21), 1.423 (1.21), 1.430 (1.94), 1.457 (1.71), 1.483 (1.32), 1.490 (1.32), 1.516 (1.34), 1.544 (0.52), 1.758 (1.60), 1.768 (1.42), 1.779 (1.11), 1.791 (1.14), 1.894 (1.37), 1.912 (1.29), 1.924 (1.42), 2.323 (0.67), 2.327 (0.93), 2.332 (0.67), 2.366 (0.98), 2.452 (7.19), 2.463 (10.44), 2.473 (8.12), 2.522 (3.02), 2.665 (0.85), 2.669 (1.11), 2.710 (1.06), 2.859 (2.43), 2.881 (2.71), 2.890 (2.66), 2.913 (2.69), 2.990 (1.14), 2.998 (1.21), 3.022 (2.38), 3.048 (1.42), 3.558 (0.98), 3.568 (1.50), 3.579 (2.04), 3.590 (2.09), 3.601 (1.53), 3.612 (0.93), 3.689 (7.39), 3.700 (10.49), 3.710 (7.68), 3.733 (2.27), 3.767 (1.81), 3.802 (1.94), 3.833 (1.81), 4.892 (7.55), 4.902 (7.50), 6.949 (5.92), 6.955 (6.20), 7.179 (3.08), 7.185 (2.92), 7.202 (3.23), 7.208 (3.13), 7.347 (3.98), 7.353 (3.95), 7.369 (4.37), 7.375 (4.47), 7.650 (3.23), 7.654 (3.36), 7.673 (2.95), 7.676 (2.79), 7.925 (7.37), 7.948 (6.69), 8.214 (16.00), 8.486 (7.26), 8.492 (7.24), 10.601 (7.39).

Example 17

tert-Butyl 3- {3-[3-( {[l-(4 -methylpiperazin- 1 -yl)cyclopropyl] carbonyl } amino) -4 - (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidine-l-carboxylate (racemate)

In a 2 mL vial, Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl ,KNl']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (5.61 mg, 5.00 μηιοΐ), N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(4-methylpiperazin-l-yl)cyclopro panecarboxamide (56.6 mg, 100 μιηοΐ), lithium hydroxide (4.79 mg, 200 μιηοΐ) and tert-butyl 3-bromopyrrolidine-l-carboxylate (racemate) (37.5 mg, 150 μιηοΐ) were loaded. The nickel pre-catalyst was then prepared in a second microwave vial. To this vial, nickel (II) chloride dimethoxyethane adduct (10.99 mg, 0.05 mmol, 0.5 equiv.) and 4,4'-di-tert-butyl-2,2'-bipyridine (16.10 mg, 0.06 mmol, 0.6 equiv.) were loaded and dissolved in 10 mL of 1 ,2-dimethoxyethane, placed under argon, sealed and sonicated for 5 minutes. 1 mL of the nickel pre- catalyst solution was syringed into the vial containing the reaction mixture. The solution was degassed a second time by sparging with argon while stirring for 10 minutes. Under a constant flow of argon, 1,1,1, 3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (31 μΐ, 100 μιηοΐ) was added to the reaction mixture using a Hamilton syringe. The cap of the microwave vial was then removed and replaced with a new cap. The reaction mixture was irradiated with one 34 W blue LED lamp in the EvoluChem™ Photochemistry Device using the 8 x 2 mL vial rack which contains an incorportated fan for cooling to maintain experiment at room temperature. The reaction mixture was allowed to stir in the device for 15 hours. The reaction mixture was charged completely on a silica gel column and a chromatographic separation was performed with a gradient of dichloromethane/methanol from 100:0 to 85: 15. The material obtained was then purified by preparative RP-HPLC on a 125x30mm with acetonitrile/water (0.2% ammonia) to provide 20 mg (30% yield) of the title compound.

LC-MS (Method 1): R _t = 0.78 min; MS (ESIpos): m/z = 657 [M+H] ⁺

Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.023 (0.44), -0.007 (3.24), 0.007 (2.12), 0.922 (0.46), 1.106 (1.63), 1.116 (3.92), 1.122 (3.85), 1.130 (1.78), 1.237 (1.96), 1.245 (4.02), 1.251 (3.25), 1.261 (1.38), 1.422 (16.00), 1.430 (14.54), 2.041 (0.60), 2.059 (0.67), 2.151 (0.83), 2.193 (15.51), 2.298 (0.73), 2.358 (0.61), 2.362 (0.72), 2.366 (0.63), 2.519 (0.76), 2.522 (0.60), 2.636 (0.45), 3.272 (0.98), 3.364 (0.43), 3.474 (0.69), 3.479 (0.80), 3.491 (0.95), 3.495 (1.30), 3.500 (0.76), 3.511 (0.59), 3.517 (0.52), 3.564 (0.47), 3.580 (0.55), 3.594 (0.47), 3.771 (1.38), 3.786 (1.33), 3.792 (1.41), 3.807 (1.09), 7.374 (2.01), 7.379 (1.93), 7.392 (2.11), 7.397 (2.12), 7.552 (1.70), 7.555 (1.75), 7.568 (1.74), 7.571 (1.81), 7.632 (2.94), 7.678 (1.73), 7.681 (1.71), 7.696 (1.59), 7.699 (1.37), 8.132 (3.83), 8.138 (0.43), 8.148 (3.43), 8.347 (0.42), 8.357 (6.37), 8.586 (4.30), 8.592 (4.22), 10.652 (3.41).

Example 18

tert-Butyl 4- {3-[3- {[2-(6-oxa-3-azabicyclo[3.1.1 ]hept-3-yl)propanoyl]amino} -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate (racemate)

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) (50.0 mg, 97 % purity, 87.6 μιηοΐ), tert-butyl piperazine-l -carboxylate (29.4 mg, 158 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.03 mg, 8.76 μιηοΐ), Di-t-butyl(2,2-diphenyl-l -methyl- 1 -cyclopropyl)phosphine (6.18 mg, 17.5 μιηοΐ) and cesium carbonate (85.7 mg, 263 μιηοΐ) was suspended in dioxane (870 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 16 h. After cooling to rt, 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 purified by RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia). The residue was purified by chromatography over a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 95:5 to deliver 31.9 mg (55 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.87 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή-NMR (600 MHz, DMSO-d6) δ [ppm] : 1.295 (2.24), 1.307 (2.24), 1.435 (16.00), 2.331 (0.48), 2.344 (0.50), 2.918 (1.39), 2.935 (0.40), 2.982 (0.43), 3.000 (0.58), 3.074 (0.41), 3.077 (0.46), 3.417 (0.71), 3.425 (1.20), 3.429 (0.99), 3.434 (1.19), 3.487 (1.00), 3.496 (1.04), 3.557 (0.63), 3.568 (0.61), 4.473 (0.53), 7.023 (0.75), 7.027 (0.76), 7.384 (0.49), 7.388 (0.49), 7.398 (0.53), 7.403 (0.55), 7.980 (0.97), 7.995 (0.86), 8.248 (2.12), 8.291 (0.79), 8.296 (0.79), 9.818 (0.89). Example 19

tert-Butyl [(3R)-1 - {3-[3- {[2RS-(6-oxa-3-azabicyclo[3.1. l]hept-3-yl)propanoyl] amino} -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate (mixture of two diastereoisomers)

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) (50.0 mg, 97 % purity, 87.6 μιηοΐ), tert-butyl (3R)- pyrrolidin-3-ylcarbamate (29.4 mg, 158 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.03 mg, 8.76 μιηοΐ), Di-t-butyl(2,2-diphenyl-l -methyl- 1 -cyclopropyl)phosphine (6.18 mg, 17.5 μmol) and cesium carbonate (85.7 mg, 263 μιηοΐ) was suspended in dioxane (870 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 16 h. After cooling to rt, 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 purified by preparative RP- HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 35.6 mg (62 % yield) of the title compound.

LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.293 (6.22), 1.307 (6.21), 1.404 (16.00), 1.433 (0.51), 1.940 (0.54), 1.953 (0.59), 1.966 (0.43), 2.174 (0.46), 2.188 (0.59), 2.201 (0.53), 2.331 (1.39), 2.347 (1.41), 2.917 (4.19), 2.933 (1.11), 2.949 (1.00), 2.962 (0.47), 2.978 (1.18), 2.999 (1.67), 3.072 (1.20), 3.075 (1.32), 3.094 (0.87), 3.098 (0.78), 3.194 (0.68), 3.203 (0.74), 3.214 (0.79), 3.224 (0.74), 3.397 (0.57), 3.400 (0.58), 3.413 (0.67), 3.512 (0.72), 3.525 (0.53), 3.531 (0.59), 3.541 (0.64), 3.555 (1.86), 3.569 (1.79), 3.583 (0.52), 3.595 (0.61), 3.608 (0.78), 3.616 (0.69), 3.628 (0.57), 4.186 (0.47), 4.197 (0.45), 4.471 (1.58), 4.481 (1.60), 6.584 (1.92), 6.588 (1.93), 6.819 (1.13), 6.824 (1.06), 6.837 (1.13), 6.842 (1.08), 7.250 (0.57), 7.262 (0.54), 7.379 (1.58), 7.385 (1.52), 7.397 (1.65), 7.402 (1.71), 7.598 (1.20), 7.601 (1.23), 7.615 (1.09), 7.618 (0.97), 7.944 (2.73), 7.962 (2.45), 8.211 (6.99), 8.281 (2.57), 8.286 (2.54), 9.827 (2.59). Example 20

tert-Butyl [(3S)-l -{3-[3- {[2RS-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)propanoyl]amino}-4 - (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate (mixture of two diastereoisomers)

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) (50.0 mg, 97 % purity, 87.6 μπιοΐ), tert-butyl (3S)- pyrrolidin-3-ylcarbamate (29.4 mg, 158 μπιοΐ), tris(dibenzylidenacetone)dipalladium (8.03 mg, 8.76 μπιοΐ), Di-t-butyl(2,2-diphenyl-l -methyl- 1 -cyclopropyl)phosphine (6.18 mg, 17.5 μmol) and cesium carbonate (85.7 mg, 263 μιηοΐ) was suspended in dioxane (870 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 16 h. After cooling to rt, 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 purified by preparative RP- HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 41.4 mg (97 % purity, 70 % yield) of the title compound.

LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.293 (6.09), 1.307 (6.07), 1.404 (16.00), 1.433 (1.02), 1.941 (0.56), 1.952 (0.59), 1.966 (0.44), 2.174 (0.46), 2.188 (0.60), 2.201 (0.54), 2.331 (1.37), 2.347 (1.41), 2.917 (4.22), 2.933 (1.10), 2.949 (1.00), 2.962 (0.46), 2.978 (1.18), 2.999 (1.67), 3.072 (1.19), 3.075 (1.31), 3.094 (0.86), 3.098 (0.77), 3.194 (0.67), 3.203 (0.76), 3.214 (0.79), 3.224 (0.74), 3.397 (0.58), 3.400 (0.59), 3.413 (0.70), 3.428 (0.40), 3.512 (0.73), 3.525 (0.54), 3.530 (0.60), 3.541 (0.64), 3.555 (1.81), 3.569 (1.75), 3.582 (0.51), 3.595 (0.60), 3.608 (0.77), 3.615 (0.70), 3.629 (0.58), 4.187 (0.47), 4.197 (0.45), 4.471 (1.60), 4.481 (1.61), 6.584 (1.90), 6.588 (1.93), 6.819 (1.11), 6.824 (1.04), 6.837 (1.11), 6.842 (1.06), 7.250 (0.58), 7.262 (0.57), 7.379 (1.51), 7.385 (1.47), 7.397 (1.57), 7.402 (1.65), 7.598 (1.18), 7.601 (1.22), 7.615 (1.08), 7.618 (0.95), 7.944 (2.65), 7.962 (2.39), 8.211 (6.61), 8.281 (2.52), 8.286 (2.48), 9.827 (2.54). Example 21

tert-Butyl [(3R)-l -{3-[3-({[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (100 mg, 181 μιηοΐ), tert-butyl (3R)-pyrrolidin-3-ylcarbamate (60.6 mg, 325 μιηοΐ), tris(dibenzylidenacetone)dipalladium (16.5 mg, 18.1 μιηοΐ), Di-t-butyl(2,2-diphenyl-l- methyl-l -cyclopropyl)phosphine (12.7 mg, 36.1 μιηοΐ) and cesium carbonate (177 mg, 542 μιηοΐ) was suspended in dioxane (1.8 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 16 h. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 76.0 mg (64 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.16 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.109 (0.83), 1.121 (2.09), 1.128 (2.18), 1.139 (0.99), 1.244 (0.41), 1.263 (1.20), 1.273 (2.31), 1.280 (1.92), 1.293 (0.91), 1.403 (16.00), 1.936 (0.48), 1.951 (0.53), 2.182 (0.53), 2.200 (0.45), 2.463 (3.68), 2.473 (3.52), 2.524 (1.30), 3.187 (0.57), 3.198 (0.64), 3.211 (0.71), 3.224 (0.66), 3.396 (0.56), 3.412 (0.61), 3.506 (0.68), 3.530 (0.50), 3.588 (0.57), 3.603 (0.70), 3.614 (0.62), 3.629 (0.53), 3.700 (3.07), 4.180 (0.46), 6.579 (1.68), 6.585 (1.67), 6.813 (0.95), 6.818 (0.85), 6.835 (0.94), 6.841 (0.93), 7.246 (0.52), 7.352 (1.29), 7.359 (1.26), 7.374 (1.36), 7.381 (1.40), 7.645 (1.05), 7.649 (1.08), 7.667 (0.92), 7.934 (2.24), 7.957 (2.01), 8.201 (5.31), 8.483 (2.49), 8.490 (2.46), 10.599 (2.15).

Example 22

tert-Butyl [(3S)-l -{3-[3-({[l -(morpholin-4-yl)cyclopropyl]carbonyl}amino)-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropanecarboxamide (100 mg, 181 μmol), tert-butyl (3S)-pyrrolidin-3-ylcarbamate (60.6 mg, 325 μιηοΐ), tris(dibenzylidenacetone)dipalladium (16.5 mg, 18.1 μιηοΐ), Di-t-butyl(2,2-diphenyl-l- methyl- 1 -cyclopropyl)phosphine (12.7 mg, 36.1 μιηοΐ) and cesium carbonate (177 mg, 542 μιηοΐ) was suspended in dioxane (1.8 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 16 h. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 83.3 mg (70 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.16 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.109 (0.82), 1.121 (2.09), 1.128 (2.20), 1.139 (1.01), 1.243 (0.46), 1.263 (1.21), 1.273 (2.32), 1.280 (1.94), 1.293 (0.92), 1.403 (16.00), 1.935 (0.49), 1.951 (0.52), 2.167 (0.42), 2.184 (0.53), 2.200 (0.47), 2.462 (3.60), 2.472 (2.94), 2.524 (0.79), 3.186 (0.60), 3.198 (0.64), 3.212 (0.68), 3.224 (0.63), 3.396 (0.54), 3.412 (0.61), 3.507 (0.68), 3.530 (0.51), 3.588 (0.58), 3.604 (0.73), 3.613 (0.65), 3.630 (0.56), 3.700 (3.14), 4.182 (0.46), 4.195 (0.42), 6.579 (1.68), 6.584 (1.68), 6.813 (0.95), 6.818 (0.89), 6.835 (0.95), 6.841 (0.89), 7.247 (0.54), 7.263 (0.49), 7.352 (1.21), 7.359 (1.16), 7.374 (1.27), 7.381 (1.30), 7.645 (1.00), 7.649 (1.02), 7.667 (0.88), 7.671 (0.79), 7.934 (2.06), 7.956 (1.84), 8.201 (4.71), 8.484 (2.23), 8.491 (2.16), 10.599 (2.13). Example 23

tert-Butyl 4- {3-[3-{[2RS-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanoyl]ami no}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate (racemate)

tert-Butyl 4-(3-amino-4- {[3-{[2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanoyl]amino}- 4- (trifluoromethoxy)phenyl]carbamoyl}phenyl)piperazine-l-carbo xylate (racemate) (93.0 mg, 140 μηιοΐ) was disolved in (diethoxymethoxy)ethane (3.1 ml, 19 mmol) and stirred at 110°C for 16 h. The solvent was then evaporated under vacuum and the residue was purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 56.5 mg (59 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.15 min; MS (ESIpos): m/z = 673 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : 1.148 (2.12), 1.165 (2.15), 1.434 (16.00), 1.798 (0.62), 1.809 (0.43), 1.933 (0.42), 2.449 (1.46), 2.581 (1.49), 3.297 (0.84), 3.423 (1.32), 3.430 (1.23), 3.437 (1.30), 3.481 (1.24), 3.496 (1.25), 4.255 (0.74), 7.024 (0.80), 7.029 (0.85), 7.230 (0.41), 7.252 (0.42), 7.258 (0.41), 7.378 (0.51), 7.385 (0.51), 7.400 (0.56), 7.407 (0.59), 7.622 (0.46), 7.626 (0.49), 7.975 (1.01), 7.998 (0.90), 8.251 (2.24), 8.374 (0.98), 8.380 (0.99), 9.696 (1.00).

Example 24

l-(4-Methylpiperazin-l-yl)-N-{5-[7-(oxetan-3-yl)-4-oxoqui nazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropanecarboxamide

In a 2 mL vial, Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl ,KNl']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (5.61 mg, 5.00 μηιοΐ) and N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(4-methylpiperazin-l-yl)cyclopro panecarboxamide (56.6 mg, 100 μιηοΐ) were loaded. The nickel pre-catalyst was then prepared in a second microwave vial. To this vial, nickel (II) chloride dimethoxyethane adduct (5.49 mg, 0.025 mmol, 0.25 equiv.) and 4,4'-di-tert-butyl-2,2'- bipyridine (8.05 mg, 0.03 mmol, 0.3 equiv.) were loaded and dissolved in 5.0 mL of 1,2- dimethoxyethane, placed under argon, sealed and sonicated for 5 minutes. 1 mL of the nickel pre- catalyst solution was syringed into the vial containing the reaction mixture. The solution was degassed a second time by sparging with argon while stirring for 10 minutes. Under a constant flow of argon, 3- bromooxetane (12 μΐ, 150 μιηοΐ), l,l,l,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (31 μΐ, 100 μιηοΐ) and 2,6-dimethylpyridine (58 μΐ, 500 μιηοΐ) were added to the reaction mixture using a Hamilton syringe. The cap of the microwave vial was removed and replaced with a new cap. The reaction mixture was irradiated with one 34 W blue LED lamp in the EvoluChem™ Photochemistry Device using the 8 x 2 mL vial rack which contains an incorportated fan for cooling to maintain experiment at room temperature. The reaction mixture was allowed to stir in the device for 15 hours. 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 18.0 mg (97 % purity, 32 % yield) of the title compound. LC-MS (Method 6): R _t = 1.01 min; MS (ESIpos): m/z = 544 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.15), 0.008 (1.30), 1.102 (1.34), 1.115 (3.58), 1.123 (4.22), 1.133 (2.02), 1.237 (1.87), 1.246 (4.14), 1.254 (3.32), 1.267 (1.46), 2.194 (16.00), 2.328 (0.61), 2.367 (0.66), 2.670 (0.52), 4.448 (0.87), 4.465 (1.69), 4.482 (1.13), 4.502 (0.49), 4.679 (4.52), 4.695 (7.64), 4.711 (4.38), 5.006 (4.88), 5.021 (4.92), 5.027 (4.95), 5.042 (3.95), 7.385 (2.23), 7.392 (2.27), 7.407 (2.53), 7.414 (2.64), 7.659 (2.01), 7.663 (2.28), 7.684 (4.17), 7.703 (1.67), 7.726 (4.20), 8.192 (4.15), 8.213 (3.79), 8.376 (9.40), 8.594 (4.52), 8.600 (4.40), 10.655 (3.69).

Example 25

tert-butyl [(3S)-l -{3-[3- {[(2RS)-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)propanoyl]am ino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate (diastereomer 1)

Enantiomer separation of 110 mg of tert-butyl [(3S)-l- {3-[3- {[2-(6-oxa-3-azabicyclo[3.1.1]heptan-3- yl)propanoyl]amino}-4-(trifluoromethoxy)phenyl]-4-oxo-3,4-di hydroquinazolin-7-yl}pyrrolidin-3- yl]carbamate (mixture of diasteromers) gave 48 mg of diastereomer 2 (chiral HPLC: Rt = 12.52 min) and 49 mg of the title compound (diastereomer 1): chiral HPLC: Rt = 10.54 min; 99% ee.

Separating method: column: YMC Chiralart Cellulose, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 50%/isopropanol 40% with 0.2% diethylamine in the isopropanol phase; temperature: 60°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: 70°C; UV detection: 235 nm.

LC-MS (Method 1): R _t = 0.94 min; MS (ESIneg): m/z = 657 [M-H] ^"

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.294 (6.39), 1.307 (6.35), 1.404 (16.00), 1.941 (0.54), 1.953 (0.61), 1.967 (0.44), 2.175 (0.48), 2.189 (0.58), 2.199 (0.54), 2.331 (1.39), 2.347 (1.43), 2.917 (4.18), 2.934 (1.12), 2.947 (0.82), 2.950 (1.02), 2.962 (0.48), 2.978 (1.19), 2.999 (1.66), 3.072 (1.22), 3.076 (1.32), 3.094 (0.88), 3.098 (0.78), 3.194 (0.68), 3.204 (0.75), 3.215 (0.82), 3.224 (0.75), 3.401 (0.65), 3.413 (0.71), 3.511 (0.75), 3.525 (0.54), 3.530 (0.61), 3.540 (0.65), 3.554 (1.90), 3.568 (1.83), 3.582 (0.54), 3.595 (0.61), 3.608 (0.78), 3.615 (0.71), 3.628 (0.58), 4.187 (0.48), 4.198 (0.44), 4.471 (1.60), 4.482 (1.60), 6.584 (1.94), 6.589 (1.94), 6.820 (1.15), 6.824 (1.09), 6.838 (1.15), 6.842 (1.09), 7.249 (0.58), 7.262 (0.54), 7.379 (1.66), 7.384 (1.60), 7.397 (1.70), 7.402 (1.80), 7.598 (1.22), 7.601 (1.26), 7.612 (0.51), 7.615 (1.12), 7.618 (0.95), 7.945 (2.85), 7.963 (2.51), 8.210 (7.24), 8.280 (2.65), 8.286 (2.62), 9.828 (2.51).

Example 26

tert-butyl [(3S)-l -{3-[3- {[(2RS)-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)propanoyl]am ino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate (diastereomer 2)

Enantiomer separation of 110 mg of tert-butyl [(3S)-l- {3-[3- {[2-(6-oxa-3-azabicyclo[3.1.1]heptan-3- yl)propanoyl]amino}-4-(trifluoromethoxy)phenyl]-4-oxo-3,4-di hydroquinazolin-7-yl}pyrrolidin-3- yl]carbamate (mixture of diastereomers) gave 49 mg of diastereomer 1 (chiral HPLC: Rt = 10.54 min) and 48 mg of the title compound (diastereomer 2): chiral HPLC: Rt = 12.52 min; 99% ee.

Separating method: column: YMC Chiralart Cellulose, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 50%/isopropanol 40% with 0.2% diethylamine in the isopropanol phase; temperature: 60°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: 70°C; UV detection: 235 nm.

Aus Enantiomerentrennung CHRM 19972-1 (Siehe Anhang) CHRM 19972-1-2 -> Fraktion 1 -> 48,0mg weiBer Feststoff CHRM 19972-1-1 -> JI U94-1 -1

LC-MS (Method 1): R _t = 0.94 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή-NMR (500 MHz, DMSO-d6) δ [ppm] : 1.293 (6.42), 1.307 (6.37), 1.403 (16.00), 1.433 (0.62), 1.941 (0.56), 1.952 (0.62), 1.966 (0.45), 2.174 (0.45), 2.188 (0.56), 2.199 (0.56), 2.331 (1.35), 2.347 (1.41), 2.917 (4.17), 2.933 (1.13), 2.949 (1.01), 2.962 (0.45), 2.978 (1.18), 2.999 (1.69), 3.072 (1.18), 3.076 (1.35), 3.094 (0.90), 3.098 (0.79), 3.193 (0.68), 3.203 (0.73), 3.214 (0.79), 3.224 (0.79), 3.361 (0.51), 3.380 (0.45), 3.397 (0.68), 3.413 (0.73), 3.429 (0.45), 3.511 (0.73), 3.525 (0.56), 3.530 (0.62), 3.540 (0.68), 3.554 (1.92), 3.568 (1.86), 3.582 (0.56), 3.595 (0.62), 3.608 (0.79), 3.616 (0.73), 3.628 (0.56), 4.187 (0.45), 4.471 (1.58), 4.482 (1.58), 6.584 (1.92), 6.589 (1.92), 6.820 (1.13), 6.825 (1.07), 6.838 (1.13), 6.843 (1.07), 7.249 (0.56), 7.262 (0.56), 7.379 (1.69), 7.384 (1.63), 7.397 (1.75), 7.402 (1.80), 7.598 (1.24), 7.601 (1.24), 7.612 (0.51), 7.615 (1.13), 7.618 (0.96), 7.945 (2.87), 7.962 (2.54), 8.210 (7.38), 8.279 (2.65), 8.284 (2.59), 9.828 (2.48). Example 27

tert-butyl [(3R)-l- {3-[3-{[(2RS)-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)propan oyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate (diastereomer 1)

Enantiomer separation of 100 mg of tert-butyl [(3R)-l- {3-[3- {[-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3- yl)propanoyl]amino}-4-(trifluoromethoxy)phenyl]-4-oxo-3,4-di hydroquinazolin-7-yl}pyrrolidin-3- yljcarbamate (mixture of diasteromers) gave 39 mg of diastereomer 2 (chiral HPLC: Rt = 13.22 min) and 39 mg of the title compound (diastereomer 1): chiral HPLC: Rt = 10.75 min; 99% ee.

Separating method: column: Daicel Chiralpak IB, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 70%/ethanol 30% with 0.2%> diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 235 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; temperature: 50°C; UV detection: 235 nm.

LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : -0.007 (4.00), 0.006 (2.74), 1.293 (6.11), 1.307 (6.08), 1.404 (16.00), 1.940 (0.56), 1.952 (0.61), 1.966 (0.43), 2.174 (0.46), 2.187 (0.61), 2.201 (0.55), 2.331 (1.39), 2.347 (1.42), 2.917 (4.20), 2.933 (1.11), 2.949 (1.00), 2.961 (0.45), 2.978 (1.18), 2.999 (1.68), 3.072 (1.21), 3.075 (1.29), 3.094 (0.87), 3.098 (0.76), 3.193 (0.68), 3.203 (0.76), 3.214 (0.81), 3.224 (0.74), 3.396 (0.57), 3.413 (0.65), 3.512 (0.73), 3.526 (0.54), 3.531 (0.59), 3.541 (0.63), 3.555 (1.81), 3.569 (1.74), 3.583 (0.50), 3.595 (0.61), 3.608 (0.77), 3.616 (0.68), 3.628 (0.57), 4.186 (0.47), 4.197 (0.45), 4.470 (1.60), 4.481 (1.60), 6.584 (1.95), 6.588 (1.90), 6.819 (1.14), 6.824 (1.06), 6.837 (1.13), 6.842 (1.06), 7.249 (0.59), 7.262 (0.55), 7.379 (1.49), 7.385 (1.43), 7.397 (1.58), 7.402 (1.61), 7.598 (1.19), 7.601 (1.20), 7.615 (1.07), 7.618 (0.92), 7.944 (2.65), 7.962 (2.39), 8.211 (6.65), 8.280 (2.59), 8.285 (2.49), 9.826 (2.64). Example 28

tert-butyl [(3R)-l- {3-[3-{[(2RS)-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)propan oyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate (diastereomer 2)

Enantiomer separation of 100 mg of tert-butyl [(3R)-l- {3-[3- {[-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3- yl)propanoyl]amino}-4-(trifluoromethoxy)phenyl]-4-oxo-3,4-di hydroquinazolin-7-yl}pyrrolidin-3- yljcarbamate (mixture of diasteromers) gave 39 mg of diastereomer 1 (chiral HPLC: Rt = 10.75 min) and 39 mg of the title compound (diastereomer 2): chiral HPLC: Rt = 13.22 min; 99% ee.

Separating method: column: Daicel Chiralpak IB, 5 μιη 250 mm x 20 mm; mobile phase: n-heptane 70%/ethanol 30% with 0.2%> diethylamine in the ethanol phase; temperature: 50°C; flow rate: 15 ml/min; UV detection: 235 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; temperature: 50°C; UV detection: 235 nm.

LC-MS (Method 1): R _t = 0.91 min; MS (ESIpos): m/z = 659 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.85), -0.007 (9.03), 0.007 (6.47), 0.117 (0.83), 1.293 (6.25), 1.307 (6.25), 1.404 (16.00), 1.941 (0.56), 1.952 (0.61), 1.966 (0.43), 2.173 (0.47), 2.186 (0.58), 2.200 (0.56), 2.331 (1.39), 2.347 (1.44), 2.917 (4.20), 2.933 (1.10), 2.948 (1.01), 2.961 (0.45), 2.978 (1.19), 2.999 (1.66), 3.075 (1.30), 3.094 (0.88), 3.098 (0.76), 3.193 (0.70), 3.203 (0.74), 3.214 (0.81), 3.224 (0.79), 3.401 (0.58), 3.413 (0.65), 3.512 (0.72), 3.530 (0.58), 3.541 (0.63), 3.555 (1.80), 3.569 (1.75), 3.582 (0.47), 3.595 (0.58), 3.608 (0.76), 3.615 (0.70), 3.628 (0.56), 4.185 (0.47), 4.470 (1.57), 4.481 (1.55), 6.584 (1.96), 6.589 (1.91), 6.819 (1.15), 6.824 (1.08), 6.837 (1.15), 6.842 (1.08), 7.249 (0.58), 7.262 (0.56), 7.379 (1.42), 7.384 (1.33), 7.396 (1.46), 7.402 (1.48), 7.597 (1.21), 7.600 (1.19), 7.615 (1.03), 7.618 (0.92), 7.944 (2.76), 7.962 (2.47), 8.210 (6.99), 8.280 (2.70), 8.285 (2.58), 9.826 (2.47). Example 29

tert-butyl [(3R)-l- {3-[3-{[l -(4-methylpiperazin- 1 -yl)cyclopropane- 1 -carbonyl] amino } -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (115 mg, 203 μιηοΐ), tert-butyl (3R)-pyrrolidin-3- ylcarbamate (68.1 mg, 365 μιηοΐ), tris(dibenzylidenacetone)dipalladium (18.6 mg, 20.3 μιηοΐ), xantphos (23.5 mg, 40.6 μιηοΐ) and cesium carbonate (198 mg, 609 μιηοΐ) was suspended in dioxane (2.0 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 65°C for 16 h. After cooling to rt, the reaction mixture was filtered through a pad of celite eluting with EtOAc. The filtrate was collected and partitioned between water and EtOAc. After extractive work-up, the combined organic layers were washed with brine and filtered through a water-removing filter. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/EtOAc from 100:0 to 0: 100, followed by a gradient of dichloromethane/methanol from 100:0 to 90: 10. The material obtained was purified by RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 95.5 mg (70 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.39 min; MS (ESIneg): m/z = 670 [M-H] ^"

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (2.67), 0.006 (1.64), 1.104 (0.92), 1.114 (2.45), 1.120 (2.47), 1.128 (1.16), 1.233 (1.18), 1.241 (2.58), 1.247 (2.12), 1.257 (0.89), 1.402 (16.00), 1.938 (0.58), 1.950 (0.62), 1.963 (0.44), 2.172 (0.67), 2.191 (10.21), 2.208 (0.50), 3.191 (0.69), 3.200 (0.76), 3.211 (0.80), 3.221 (0.74), 3.397 (0.59), 3.410 (0.66), 3.508 (0.73), 3.522 (0.53), 3.527 (0.56), 3.591 (0.61), 3.604 (0.77), 3.612 (0.69), 3.625 (0.56), 4.184 (0.49), 4.194 (0.46), 6.578 (1.93), 6.583 (1.88), 6.814 (1.11), 6.819 (1.04), 6.832 (1.10), 6.837 (1.02), 7.246 (0.59), 7.259 (0.56), 7.340 (1.49), 7.345 (1.42), 7.358 (1.51), 7.363 (1.52), 7.641 (1.14), 7.643 (1.14), 7.658 (1.05), 7.661 (0.91), 7.935 (2.54), 7.953 (2.25), 8.200 (6.03), 8.537 (2.84), 8.542 (2.73), 10.634 (2.38). Example 30

tert-butyl [(3R)- 1 - {3-[4-(difluoromethoxy)-3 - { [ 1 -(morpholin-4-yl)cyclopropane- 1 - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyrrolidin-3 -yljcarbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (60.0 mg, 94 % purity, 105 μιηοΐ), tert-butyl (3R)-pyrrolidin-3- ylcarbamate (37.6 mg, 202 μιηοΐ) and cesium carbonate (110 mg, 337 μιηοΐ) in anhydrous 1,4-dioxan (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (10.3 mg, 11.3 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (7.98 mg, 22.7 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly 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 one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (0.5% ammonia) to afford 30.0 mg (44 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.03 min; MS (ESIpos): m/z = 641 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.47), 1.097 (0.94), 1.107 (2.56), 1.113 (2.52), 1.121 (1.19), 1.241 (1.20), 1.249 (2.66), 1.255 (2.21), 1.265 (0.94), 1.402 (16.00), 1.937 (0.56), 1.949 (0.59), 1.962 (0.44), 2.170 (0.47), 2.184 (0.58), 2.197 (0.55), 2.452 (2.97), 3.189 (0.68), 3.198 (0.75), 3.210 (0.79), 3.219 (0.73), 3.396 (0.62), 3.409 (0.68), 3.507 (0.73), 3.520 (0.55), 3.526 (0.58), 3.590 (0.61), 3.603 (0.78), 3.611 (0.68), 3.623 (0.58), 3.722 (3.41), 4.182 (0.47), 6.575 (1.93), 6.579 (1.92), 6.811 (1.14), 6.816 (1.06), 6.829 (1.13), 6.834 (1.06), 7.245 (0.58), 7.258 (0.58), 7.273 (1.60), 7.278 (1.49), 7.290 (1.64), 7.295 (1.67), 7.331 (1.25), 7.454 (2.07), 7.472 (1.76), 7.478 (2.80), 7.625 (1.14), 7.932 (2.69), 7.950 (2.40), 8.163 (6.77), 8.453 (3.07), 8.458 (3.01), 10.661 (2.51).

Example 31

tert-butyl [(3 S)-l - {3 -[4-(difluoromethoxy)-3- { [ 1 -(morpholin-4-yl)cyclopropane- 1 - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyrrolidin-3 -yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (60.0 mg, 112 μιηοΐ), tert-butyl (3S)-pyrrolidin-3-ylcarbamate (37.6 mg, 202 μmol) and cesium carbonate (110 mg, 336 μιηοΐ) in anhydrous 1,4-dioxan (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (10.3 mg, 11.2 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (7.90 mg, 22.4 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly 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 one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (0.5% ammonia) to afford 34.0 mg (47 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.03 min; MS (ESIpos): m/z = 641 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.45), 1.097 (0.93), 1.107 (2.54), 1.113 (2.54), 1.121 (1.19), 1.241 (1.17), 1.249 (2.65), 1.255 (2.20), 1.265 (0.96), 1.402 (16.00), 1.937 (0.55), 1.949 (0.59), 1.962 (0.42), 2.170 (0.45), 2.184 (0.58), 2.197 (0.53), 2.452 (2.89), 3.189 (0.69), 3.199 (0.74), 3.210 (0.80), 3.219 (0.74), 3.396 (0.59), 3.409 (0.67), 3.507 (0.72), 3.520 (0.53), 3.525 (0.56), 3.590 (0.59), 3.603 (0.77), 3.610 (0.69), 3.623 (0.58), 3.722 (3.37), 3.730 (2.36), 4.183 (0.45), 6.575 (1.91), 6.579 (1.91), 6.811 (1.12), 6.816 (1.06), 6.829 (1.12), 6.834 (1.08), 7.245 (0.56), 7.258 (0.56), 7.273 (1.59), 7.278 (1.51), 7.290 (1.65), 7.295 (1.69), 7.331 (1.27), 7.454 (2.10), 7.472 (1.77), 7.478 (2.79), 7.625 (1.17), 7.932 (2.73), 7.950 (2.44), 8.163 (6.87), 8.453 (3.08), 8.458 (3.07), 10.661 (2.50).

Example 32

tert-butyl 4- {3 - [4-(difluoromethoxy)-3 - { [ 1 -(morpholin-4-yl)cyclopropane- 1 -carbonyl] amino } phenyl] -4- oxo-3,4-dihydroquinazolin-7-yl}piperazine-l-carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (60.0 mg, 112 μιηοΐ), tert-butyl piperazine-l-carboxylate (37.6 mg, 202 μιηοΐ) and cesium carbonate (110 mg, 336 μιηοΐ) in anhydrous 1,4-dioxan (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (10.3 mg, 11.2 μιηοΐ) and di-tert-butyl(l-methyl-2,2-diphenylcyclopropyl)phosphine (7.90 mg, 22.4 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly 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 one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (0.5% ammonia) to afford 20.0 mg (28 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.09 min; MS (ESIpos): m/z = 641 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.107 (0.91), 1.113 (0.89), 1.121 (0.42), 1.242 (0.43), 1.250 (0.95), 1.256 (0.79), 1.433 (16.00), 2.452 (1.03), 3.409 (0.68), 3.418 (1.18), 3.424 (1.03), 3.429 (1.15), 3.481 (1.03), 3.492 (1.03), 3.715 (0.85), 3.723 (1.19), 7.015 (0.76), 7.020 (0.74), 7.244 (0.40), 7.278 (0.54), 7.284 (0.52), 7.296 (0.58), 7.301 (0.60), 7.333 (0.45), 7.462 (0.73), 7.480 (1.46), 7.627 (0.42), 7.968 (1.03), 7.986 (0.91), 8.208 (2.49), 8.463 (1.10), 8.468 (1.07), 10.667 (0.85).

Example 33

tert-butyl (1 -{3-[4-(difluoromethoxy)-3- {[1 -(morpholin-4-yl)cyclopropane-l -carbonyl] amino} phenyl] - 4-oxo-3,4-dihydroquinazolin-7-yl}azetidin-3-yl)carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (60.0 mg, 112 μιηοΐ), tert-butyl azetidin-3-ylcarbamate (34.7 mg, 202 μιηοΐ) and cesium carbonate (110 mg, 336 μιηοΐ) in anhydrous 1,4-dioxan (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (10.3 mg, 11.2 μιηοΐ) and di-tert-butyl(l-methyl-2,2-diphenylcyclopropyl)phosphine (7.90 mg, 22.4 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly 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 one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (0.5% ammonia) to afford 19.0 mg (27 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.96 min; MS (ESIpos): m/z = 627 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.106 (0.91), 1.112 (0.90), 1.120 (0.42), 1.241 (0.42), 1.249 (0.94), 1.255 (0.78), 1.402 (16.00), 2.451 (1.04), 3.713 (0.86), 3.722 (1.20), 3.730 (0.84), 3.783 (0.51), 3.795 (0.62), 3.799 (0.62), 3.811 (0.53), 4.253 (0.76), 6.477 (0.82), 6.481 (0.83), 6.647 (0.42), 6.664 (0.42), 7.268 (0.54), 7.273 (0.53), 7.285 (0.59), 7.290 (0.61), 7.329 (0.45), 7.455 (0.74), 7.473 (0.68), 7.476 (1.05), 7.623 (0.62), 7.938 (1.09), 7.955 (0.98), 8.178 (2.43), 8.451 (1.09), 8.456 (1.08), 10.663 (0.88).

Example 34

tert-butyl [(3S)-l -{3-[4-(difluoromethoxy)-3-({[l-(4-methylpiperazin-l - yl)cyclopropyl]carbonyl}amino)phenyl]-4-oxo-3,4-dihydroquina zolin-7-yl}pyrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (60.0 mg, 109 μιηοΐ), tert-butyl (3S)-pyrrolidin-3- ylcarbamate (36.7 mg, 197 μιηοΐ) and cesium carbonate (107 mg, 328 μιηοΐ) in anhydrous 1,4-dioxan (1.1 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (10.0 mg, 10.9 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (7.71 mg, 21.9 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 and followed by a gradient ethyl acetate/methanol from 97:3 to 85: 15. The product fractions were collected and purified one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 20.0 mg (28 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.34 min; MS (ESIneg): m/z = 652 [M-H] ^"

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.085 (0.91), 1.095 (2.40), 1.101 (2.46), 1.109 (1.23), 1.202 (1.17), 1.210 (2.59), 1.216 (2.07), 1.226 (0.91), 1.400 (16.00), 1.935 (0.58), 1.947 (0.58), 1.961 (0.45), 2.169 (0.52), 2.183 (0.78), 2.200 (9.39), 2.442 (2.07), 3.187 (0.65), 3.197 (0.71), 3.208 (0.78), 3.217 (0.71), 3.364 (0.71), 3.374 (0.58), 3.394 (0.78), 3.406 (0.84), 3.422 (0.45), 3.505 (0.78), 3.518 (0.58), 3.523 (0.58), 3.588 (0.65), 3.601 (0.78), 3.608 (0.71), 3.622 (0.58), 4.179 (0.52), 6.572 (1.94), 6.577 (1.94), 6.810 (1.10), 6.815 (1.04), 6.828 (1.10), 6.833 (1.04), 7.243 (0.58), 7.259 (1.88), 7.264 (1.62), 7.277 (1.62), 7.282 (1.68), 7.325 (1.23), 7.444 (2.07), 7.462 (1.68), 7.472 (2.72), 7.619 (1.17), 7.930 (2.66), 7.948 (2.40), 8.159 (6.80), 8.474 (2.98), 8.479 (2.98), 10.677 (2.20). Example 35

tert-butyl [(3R)-l- {3-[4-(methoxymethyl)-3- {[l-(morpholin-4-yl)cyclopropane-l - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyrrolidin-3 -yljcarbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phe nyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 97.4 μιηοΐ), tert-butyl (3R)-pyrrolidin-3-ylcarbamate (32.7 mg, 175 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.46 mg, 4.87 μιηοΐ), xantphos (5.64 mg, 9.74 μιηοΐ) and cesium carbonate (95.2 mg, 292 μιηοΐ) was suspended in dioxane (970 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 22 h. After this time, additional tert-butyl (3R)-pyrrolidin-3-ylcarbamate (65.3 mg, 351 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.46 mg, 4.87 μιηοΐ) and xantphos (5.64 mg, 9.74 μιηοΐ) were added and the reaction mixture was degassed again py bubbling argon thorugh it before stirring it at 80°C for further 24 h. After cooling to rt, the reaction mixture was partitioned between water and dichloromethane. After extractive work-up, the combined organic layers were dried over Na2S04, filtered and evaporated. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was purified by RP-HPLC 125x30mm with acetonitrile/water to deliver 12.5 mg (21 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.95 min; MS (ESIpos): m/z = 619 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.71), 1.074 (0.84), 1.086 (2.02), 1.094 (2.23), 1.103 (1.08), 1.199 (1.13), 1.209 (2.28), 1.216 (1.84), 1.229 (0.88), 1.403 (16.00), 1.935 (0.51), 1.950 (0.55), 1.967 (0.40), 2.167 (0.43), 2.182 (0.54), 2.197 (0.50), 2.440 (3.15), 3.186 (0.60), 3.198 (0.65), 3.212 (0.70), 3.224 (0.65), 3.339 (13.69), 3.371 (0.42), 3.395 (0.56), 3.411 (0.64), 3.506 (0.69), 3.529 (0.51), 3.587 (0.57), 3.603 (0.73), 3.612 (0.64), 3.628 (0.52), 3.716 (2.82), 3.727 (3.77), 3.738 (2.55), 4.182 (0.48), 4.644 (4.57), 6.575 (1.66), 6.581 (1.65), 6.810 (0.94), 6.815 (0.88), 6.832 (0.94), 6.838 (0.87), 7.194 (1.14), 7.200 (1.12), 7.215 (1.23), 7.220 (1.25), 7.246 (0.60), 7.261 (0.55), 7.491 (1.73), 7.511 (1.53), 7.934 (1.92), 7.956 (1.74), 8.161 (4.30), 8.282 (2.06), 8.287 (2.02), 10.706 (1.94).

Example 36

tert-butyl [(3 S)-l - {3 -[4-(methoxymethyl)-3 - { [1 -(morpholin-4-yl)cyclopropane- 1 - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyrrolidin-3 -yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phe nyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 97.4 μιηοΐ), tert-butyl (3S)-pyrrolidin-3-ylcarbamate (32.7 mg, 175 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.46 mg, 4.87 μιηοΐ), xantphos (5.64 mg, 9.74 μιηοΐ) and cesium carbonate (95.2 mg, 292 μιηοΐ) was suspended in dioxane (970 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 22 h. After this time, additional tert-butyl (3S)-pyrrolidin-3-ylcarbamate (65.3 mg, 351 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.46 mg, 4.87 μιηοΐ) and xantphos (5.64 mg, 9.74 μιηοΐ) were added and the reaction mixture was degassed again py bubbling argon thorugh it before stirring it at 80°C for further 24 h. After cooling to rt, the reaction mixture was partitioned between water and dichloromethane. After extractive work-up, the combined organic layers were dried over Na2S04, filtered and evaporated. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was purified by RP-HPLC 125x30mm with acetonitrile/water to deliver 7.5 mg (12 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.95 min; MS (ESIpos): m/z = 619 [M+H] ⁺

Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.077 (0.90), 1.087 (2.29), 1.093 (2.39), 1.101 (1.12), 1.201 (1.16), 1.209 (2.48), 1.215 (2.08), 1.225 (0.96), 1.234 (0.78), 1.402 (14.79), 1.938 (0.55), 1.949 (0.59), 1.962 (0.42), 2.171 (0.44), 2.184 (0.58), 2.197 (0.52), 3.190 (0.67), 3.200 (0.76), 3.210 (0.79), 3.220 (0.77), 3.339 (16.00), 3.378 (0.61), 3.397 (0.75), 3.409 (0.79), 3.424 (0.45), 3.507 (0.75), 3.526 (0.58), 3.590 (0.59), 3.603 (0.74), 3.610 (0.69), 3.624 (0.56), 3.718 (2.91 ), 3.727 (4.16), 3.735 (2.81), 4.184 (0.48), 4.644 (4.98), 6.576 (1.70), 6.580 (1.74), 6.813 (0.93), 6.817 (0.92), 6.831 (0.99), 6.835 (0.96), 7.197 (1.14), 7.201 (1.13), 7.213 (1.21), 7.217 (1.26), 7.246 (0.60), 7.259 (0.60), 7.492 (1.80), 7.508 (1.65), 7.936 (1.96), 7.953 (1.85), 8.161 (4.55), 8.281 (2.19), 8.286 (2.23), 10.706 (2.05).

Example 37

tert-butyl 4- {3 - [4-(methoxymethyl) -3 - { [ 1 -(morpholin-4-yl)cyclopropane- 1 -carbonyl] amino } phenyl] -4- oxo-3,4-dihydroquinazolin-7-yl}piperazine-l-carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phe nyl]-l-(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 97.4 μιηοΐ), tert-butyl piperazine-l-carboxylate (32.7 mg, 175 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.46 mg, 4.87 μιηοΐ), xantphos (5.64 mg, 9.74 μιηοΐ) and cesium carbonate (95.2 mg, 292 μιηοΐ) was suspended in dioxane (970 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 17 h. After cooling to rt, the reaction mixture was partitioned between water and dichloromethane. After extractive work-up, the combined organic layers were dried over Na2S04, filtered and evaporated. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10. The material obtained was purified by RP-HPLC 125x30mm with acetonitrile/water to deliver 14.5 mg (24 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.07 min; MS (ESIpos): m/z = 619 [M+H] 1+ Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 1.086 (1.05), 1.093 (1.20), 1.103 (0.60), 1.201 (0.55), 1.210 (1.20), 1.217 (1.02), 1.230 (0.48), 1.434 (16.00), 3.339 (6.81), 3.417 (1.63), 3.425 (1.57), 3.431 (1.51), 3.480 (1.42), 3.487 (1.50), 3.494 (1.54), 3.716 (1.44), 3.727 (2.08), 3.738 (1.47), 4.647 (2.44), 7.016 (0.89), 7.022 (0.93), 7.201 (0.52), 7.206 (0.53), 7.225 (0.99), 7.247 (0.48), 7.252 (0.47), 7.499 (0.87), 7.518 (0.78), 7.968 (0.95), 7.991 (0.85), 8.207 (1.98), 8.291 (1.00), 8.296 (1.01), 10.710 (1.02).

Example 38

tert-butyl [(3R)-l- {8-fluoro-3-[3- {[l -(morpholin-4-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (80.0 mg, 140 μιηοΐ), tert-butyl (3R)-pyrrolidin-3- ylcarbamate (46.9 mg, 252 μιηοΐ) and cesium carbonate (137 mg, 420 μιηοΐ) in anhydrous 1,4-dioxane (1.2 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (12.8 mg, 14.0 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (9.87 mg, 28.0 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. Due to partial conversion of the starting material, additional tert-butyl (3R)-pyrrolidin-3-ylcarbamate (23.5 mg, 126 μιηοΐ), Tris(dibenzylidenacetone)dipalladium (6.41 mg, 7.00 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (4.94 mg, 14.0 μιηοΐ) were added and the reaction mixture was allowed to stir for 15 h at 95 °C. 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. The product fractions were collected and purified one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (0.5 % ammonia) to afford 8.00 mg (8 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.23 min; MS (ESIpos): m/z = 677 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : 1.109 (0.64), 1.121 (1.75), 1.129 (1.87), 1.139 (0.87), 1.234 (0.80), 1.265 (0.89), 1.275 (1.92), 1.282 (1.66), 1.295 (0.68), 1.400 (16.00), 1.891 (0.45), 1.905 (0.47), 2.113 (0.47), 2.128 (0.42), 2.463 (2.94), 3.389 (0.52), 3.400 (0.46), 3.415 (0.55), 3.549 (0.44), 3.567 (0.49), 3.662 (0.60), 3.699 (2.95), 3.765 (0.57), 4.121 (0.42), 6.928 (0.55), 6.950 (0.95), 6.971 (0.58), 7.232 (0.45), 7.248 (0.45), 7.366 (0.81), 7.373 (0.80), 7.388 (0.90), 7.395 (0.93), 7.665 (0.79), 7.684 (0.70), 7.768 (1.16), 7.790 (1.07), 8.261 (2.78), 8.502 (1.55), 8.509 (1.56), 10.604 (1.79).

Example 39

tert-butyl [(3 S)- 1 - { 8 -fluoro-3 - [3 - { [ 1 -(4-methylpiperazin- 1 -yl)cyclopropane- 1 -carbonyl] amino } -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (55.0 mg, 94.1 μιηοΐ), tert-butyl (3S)-pyrrolidin-3- ylcarbamate (31.6 mg, 169 μιηοΐ) and cesium carbonate (92.0 mg, 282 μιηοΐ) in anhydrous 1,4-dioxane (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (8.62 mg, 9.41 μιηοΐ) and Xantphos (10.9 mg, 18.8 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient cyclohexane/ethyl acetate from 90: 10 to 0: 100 and then with a gradient dichloromethane/methanol from 97:3 to 85: 15 (+ 0.2 % ammonia). The product fractions were collected and purified one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2 % ammonia) to afford 30.0 mg (46 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.47 min; MS (ESIpos): m/z = 690 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.59), 0.008 (0.54), 1.101 (0.58), 1.114 (1.61), 1.121 (1.79), 1.131 (0.86), 1.234 (1.32), 1.243 (1.91), 1.251 (1.53), 1.264 (0.65), 1.400 (16.00), 1.891 (0.40), 1.905 (0.45), 2.113 (0.44), 2.192 (7.14), 3.389 (0.44), 3.415 (0.47), 3.568 (0.42), 3.660 (0.47), 3.765 (0.48), 6.928 (0.58), 6.950 (0.92), 6.971 (0.61), 7.233 (0.41), 7.247 (0.40), 7.352 (0.99), 7.358 (0.97), 7.374 (1.05), 7.380 (1.12), 7.656 (0.79), 7.660 (0.83), 7.678 (0.73), 7.681 (0.67), 7.768 (1.18), 7.790 (1.07), 8.262 (3.39), 8.553 (1.89), 8.560 (1.91), 10.641 (1.73). Example 40

tert-butyl 4- {8-fluoro-3-[3- {[l-(morpholin-4-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate

A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (60.0 mg, 105 μιηοΐ), tert-butyl piperazine-l-carboxylate (35.2 mg, 189 μιηοΐ) and cesium carbonate (103 mg, 315 μιηοΐ) in anhydrous 1,4-dioxane (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (9.62 mg, 10.5 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (7.40 mg, 21.0 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. Due to partial conversion of the starting material, additional tert-butyl piperazine-l-carboxylate (17.6 mg, 94.5 μιηοΐ), Tris(dibenzylidenacetone)dipalladium (4.81 mg, 5.25 μιηοΐ) and di-tert-butyl(l -methyl-2,2- diphenylcyclopropyl)phosphine (3.70 mg, 10.5 μιηοΐ) were added and the reaction mixture was allowed to stir overnight at 95 °C. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 98:2 to 85: 15 (+ 0.2 % ammonia). The product fractions were collected and purified one more time by preparative RP- HPLC 125x30mm with acetonitrile/water (0.5 % ammonia) to afford 10.0 mg (14 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.24 min; MS (ESIpos): m/z = 677 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.48), -0.008 (0.67), 0.008 (0.58), 1.120 (0.90), 1.128 (0.97), 1.138 (0.46), 1.234 (1.02), 1.266 (0.47), 1.275 (1.04), 1.283 (0.85), 1.434 (16.00), 3.213 (0.87), 3.225 (1.27), 3.238 (1.05), 3.520 (1.15), 3.700 (1.31), 7.301 (0.48), 7.377 (0.52), 7.383 (0.52), 7.398 (0.56), 7.405 (0.59), 7.678 (0.41), 7.682 (0.43), 7.885 (0.54), 7.905 (0.48), 8.331 (1.74), 8.525 (0.96), 8.531 (0.96), 10.612 (0.92). Example 11

tert-butyl [(3R)- 1 - { 8-fluoro-3 - [3 - { [ 1 -(4-methylpiperazin- 1 -yl)cyclopropane- 1 -carbonyl] amino } -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (55.0 mg, 94.1 μmol), tert-butyl (3R)-pyrrolidin-3- ylcarbamate (31.6 mg, 169 μιηοΐ) and cesium carbonate (92.0 mg, 282 μιηοΐ) in anhydrous 1,4-dioxane (1.0 ml) was degassed in a microwave vial by passing argon through it for 5 min. Tris(dibenzylidenacetone)dipalladium (8.62 mg, 9.41 μιηοΐ) and Xantphos (10.9 mg, 18.8 μιηοΐ) were added, the vial was sealed and the reaction mixture was allowed to stir at 95 °C overnight. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient dichloromethane/methanol from 97:3 to 85: 15 (+ 0.2 % ammonia). The product fractions were collected and purified one more time by preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to afford 22.0 mg (34 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.48 min; MS (ESIpos): m/z = 690 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.81), 0.008 (0.64), 1.104 (0.54), 1.117 (1.52), 1.124 (1.70), 1.134 (0.80), 1.232 (0.92), 1.242 (1.89), 1.249 (1.47), 1.262 (0.63), 1.400 (16.00), 1.890 (0.41), 1.905 (0.44), 2.113 (0.46), 2.128 (0.43), 2.215 (1.25), 2.469 (1.89), 3.388 (0.43), 3.415 (0.46), 3.564 (0.42), 3.661 (0.46), 3.678 (0.41), 3.765 (0.47), 6.928 (0.58), 6.950 (0.94), 6.971 (0.59), 7.232 (0.43), 7.357 (0.74), 7.363 (0.76), 7.379 (0.85), 7.385 (0.92), 7.655 (0.81), 7.658 (0.82), 7.677 (0.75), 7.680 (0.67), 7.768 (1.18), 7.790 (1.08), 8.261 (3.46), 8.538 (0.52).

Example 42

N-[5- {7-[trans-2-(hydroxymethyl)cyclopropyl]-4-oxoquinazolin-3(4H )-yl} -2- (trifluoromethoxy)phenyl] - 1 -(morpholin-4-yl)cyclopropane- 1 -carboxamide (racemate)

To a solution of N-[5- {7-[trans-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopro pyl]-4- oxoquinazolin-3 (4H)-yl} -2-(trifluoromethoxy)phenyl] - 1 -(morpholin-4-yl)cyclopropane- 1 -carboxamide (48.0 mg, 96 % purity, 69.9 μηιοΐ) in THF (1.6 ml) at 0 °C was added N,N,N-tributylbutan-l-aminium fluoride (1.0M in THF) (73 μΐ, 1.0 M, 73 μιηοΐ) and the reaction mixture was allowed to stir for 18 h while warming up to rt. The mixture was then submitted to preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid). The residue was then partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum to afford 28.0 mg (99 % purity, 74 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.76 min; MS (ESIpos): m/z = 545 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.44), -0.042 (0.68), 0.008 (2.17), 0.842 (0.88), 0.936 (0.76), 1.034 (5.05), 1.052 (8.26), 1.069 (6.02), 1.108 (2.85), 1.120 (7.70), 1.128 (8.38), 1.138 (3.89), 1.175 (0.60), 1.264 (3.89), 1.275 (8.42), 1.282 (7.10), 1.295 (2.97), 1.439 (1.28), 1.454 (2.05), 1.467 (1.92), 1.483 (1.20), 1.989 (0.72), 2.007 (1.56), 2.024 (2.77), 2.035 (2.45), 2.052 (1.28), 2.076 (0.64), 2.330 (1.44), 2.369 (1.60), 2.464 (11.83), 2.474 (9.46), 2.673 (1.60), 2.713 (1.56), 3.356 (2.17), 3.371 (2.53), 3.385 (3.13), 3.399 (3.09), 3.414 (1.84), 3.506 (1.88), 3.520 (3.65), 3.534 (3.33), 3.549 (2.61), 3.563 (1.28), 3.700 (11.43), 4.716 (1.88), 4.728 (3.53), 4.743 (1.88), 7.293 (3.89), 7.297 (4.05), 7.314 (4.05), 7.318 (4.33), 7.386 (4.21), 7.393 (4.25), 7.415 (11.99), 7.675 (3.49), 7.678 (3.53), 7.696 (3.17), 7.700 (3.01), 8.038 (7.06), 8.059 (6.62), 8.320 (16.00), 8.517 (7.26), 8.524 (7.34), 10.610 (7.82).

Example 43

l-(morpholin-4-yl)-N- {5-[7-(2-oxaspiro[3.3]heptan-6-yl)-4-oxoquinazolin-3(4H)-yl] -2- (trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide

4,4'-Di-tert-butyl-2,2'-bipyridine (3.54 mg, 13.2 μηιοΐ) and (l,2-Dimethoxyethane)nickel dichloride (CAS 29046-78-4) (2.42 mg, 11.0 μιηοΐ) were charged under argon in a vial and suspended in dry methanol (0.7 ml). This mixture was stirred at rt for 30 min while an argon stream was passed through it until the solvent was evaporated and the resulting solid was further dried under vacuum for 2 h. To this solid under argon were then subsequently added N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(morpholin-4-yl)cyclopropane-l-c arboxamide (122 mg, 220 μιηοΐ), Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl ,KNl ']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (7.41 mg, 6.60 μιηοΐ), sodium carbonate (93.3 mg, 880 μιηοΐ), (trifluoromethyl)benzene (4.0 ml) and N,N-dimethylacetamide (1.0 ml), followed by the addition of 6-bromo-2- oxaspiro[3.3]heptane (73 μΐ, 660 μιηοΐ) and 1,1, 1,3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (75 μΐ, 240 μιηοΐ). An argon stream was passed through the suspension for 5 min and the reaction was stirred at rt for 16 h while irradiated with a 34W blue LED lamp in the EvoluChem™ Photochemistry Device at a distance of 7 cm. The reaction mixture was filtered through a silica column eluting with a mixture of dichloromethane/methanol 10: 1. The material obtained was then purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% formic acid) followed by a chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate from 90: 10 to 0: 100 to provide 45.7 mg (93 % purity, 34 % yield) of the title product.

LC-MS (Method 6): R _t = 2.01 min; MS (ESIpos): m/z = 571 [M+H] ⁺

Ή-ΝΜΡν (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.48), -0.008 (4.48), 0.008 (4.37), 0.146 (0.46), 1.107 (1.83), 1.119 (5.12), 1.127 (5.72), 1.137 (2.66), 1.233 (0.45), 1.264 (2.53), 1.275 (5.71), 1.282 (5.00), 1.295 (2.08), 2.041 (1.00), 2.328 (2.80), 2.334 (1.85), 2.351 (4.04), 2.359 (4.32), 2.375 (2.00), 2.382 (2.94), 2.463 (7.70), 2.473 (5.92), 2.523 (1.70), 2.670 (3.12), 2.677 (2.05), 2.692 (3.35), 2.701 (3.01), 2.715 (1.86), 2.722 (2.41), 3.474 (0.48), 3.495 (1.62), 3.517 (2.31), 3.540 (1.47), 3.562 (0.41), 3.701 (7.65), 4.512 (16.00), 4.729 (15.93), 7.384 (2.81), 7.390 (2.82), 7.406 (3.09), 7.412 (3.28), 7.445 (2.43), 7.449 (2.66), 7.466 (2.60), 7.469 (2.90), 7.533 (4.83), 7.677 (2.34), 7.681 (2.49), 7.699 (2.12), 7.703 (2.03), 8.105 (4.77), 8.125 (4.45), 8.341 (10.67), 8.525 (5.04), 8.531 (5.12), 10.613 (5.09). Example 44

l-(morpholin-4-yl)-N- {5-[7-(oxan-4-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide

4,4'-Di-tert-butyl-2,2'-bipyridine (3.87 mg, 14.4 μηιοΐ) and (l,2-Dimethoxyethane)nickel dichloride (CAS 29046-78-4) (2.64 mg, 12.0 μιηοΐ) were charged under argon in a vial and suspended in dry methanol (0.7 ml). This mixture was stirred at rt for 30 min while an argon stream was passed through it until the solvent was evaporated and the resulting solid was further dried under vacuum for 2 h. To this solid under argon were then subsequently added N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2- (trifluoromethoxy)phenyl]-l-(morpholin-4-yl)cyclopropane-l -carboxamide (133 mg, 240 μιηοΐ), Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-KNl ,KNl ']bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-KN]phenyl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (8.09 mg, 7.20 μιηοΐ), sodium carbonate (102 mg, 960 μιηοΐ), (trifluoromethyl)benzene (4.8 ml) and N,N-dimethylacetamide (1.2 ml), followed by the addition of 4-bromotetrahydropyran (109 mg, 660 μιηοΐ) and 1,1,1, 3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (81 μΐ, 260 μιηοΐ). An argon stream was passed through the suspension for 5 min and the reaction was stirred at rt for 16 h while irradiated with a 34W blue LED lamp in the EvoluChem™ Photochemistry Device at a distance of 7 cm. The reaction mixture was filtered through a silica column eluting with a mixture of dichloromethane/methanol 10: 1. The material obtained was then purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% formic acid) to provide 42.2 mg (99 % purity, 31 % yield) of the title product.

LC-MS (Method 6): R _t = 2.03 min; MS (ESIpos): m/z = 559 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.74), -0.008 (6.67), 0.008 (6.27), 0.146 (0.70), 1.037 (0.63), 1.110 (2.46), 1.122 (6.72), 1.130 (7.48), 1.140 (3.54), 1.266 (3.27), 1.276 (7.45), 1.283 (6.25), 1.296 (2.55), 1.408 (1.90), 1.715 (0.65), 1.736 (2.20), 1.747 (1.90), 1.765 (6.42), 1.775 (8.61), 1.788 (5.83), 1.795 (5.74), 2.328 (0.81), 2.366 (0.65), 2.465 (9.98), 2.476 (8.01), 2.670 (0.83), 2.710 (0.62), 2.966 (0.62), 2.993 (1.28), 3.005 (1.85), 3.019 (1.43), 3.449 (2.13), 3.461 (1.95), 3.477 (4.07), 3.485 (4.15), 3.505 (2.06), 3.513 (2.45), 3.702 (10.02), 3.972 (4.96), 3.999 (3.56), 7.380 (4.01), 7.386 (4.07), 7.402 (4.49), 7.408 (4.65), 7.532 (3.52), 7.536 (4.00), 7.553 (3.66), 7.557 (4.38), 7.598 (7.15), 7.601 (6.76), 7.681 (3.22), 7.685 (3.40), 7.703 (2.99), 7.707 (2.80), 8.123 (6.92), 8.143 (6.39), 8.345 (16.00), 8.359 (0.77), 8.531 (7.38), 8.537 (7.43), 10.616 (6.71).

Example 45

tert-butyl 6- {3-[3 - {[1 -(morpholin-4-yl)cyclopropane-l-carbonyl] amino} -4-(trifluoromethoxy)phenyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-2,6-diazaspiro[3.3]heptane-2 -carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 90.4 μιηοΐ), tert-butyl 2,6-diazaspiro[3.3]heptane-2- carboxylate (32.2 mg, 163 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.27 mg, 9.04 μιηοΐ), cBRIDP (6.37 mg, 18.1 μιηοΐ) and cesium carbonate (88.3 mg, 271 μιηοΐ) was suspended in 1,4-dioxane (900 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C overnight. After cooling to rt, the reaction mixture was directly purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 100:0 to 90: 10 followed by preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to deliver 27.0 mg (90 % purity, 40 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.26 min; MS (ESIpos): m/z = 671 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.47), 0.008 (0.44), 1.117 (0.98), 1.124 (1.05), 1.135 (0.49), 1.262 (0.45), 1.272 (1.07), 1.279 (0.90), 1.388 (16.00), 2.461 (1.52), 2.471 (1.23), 2.523 (0.85), 3.697 (1.46), 4.065 (2.13), 4.144 (5.10), 6.471 (0.96), 6.477 (1.00), 6.639 (0.52), 6.644 (0.48), 6.661 (0.52), 6.666 (0.50), 7.346 (0.54), 7.353 (0.55), 7.368 (0.57), 7.375 (0.58), 7.646 (0.46), 7.650 (0.47), 7.668 (0.42), 7.944 (1.05), 7.965 (0.96), 8.217 (2.23), 8.479 (1.06), 8.485 (1.04), 10.597 (1.01).

Example 46

tert-butyl 4- {6-fluoro-3-[3- {[l-(4-methylpiperazin-l -yl)cyclopropane-l-carbonyl]amino} -4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate

A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (850 mg, 1.45 mmol), tert-butyl piperazine-1- carboxylate (488 mg, 2.62 mmol), tris(dibenzylidenacetone)dipalladium (133 mg, 145 μιηοΐ), Xantphos (168 mg, 291 μιηοΐ) and cesium carbonate (1.42 g, 4.36 mmol) was suspended in THF (14 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 65°C overnight. After addition of more tris(dibenzylidenacetone)dipalladium (133 mg, 145 μιηοΐ) and Xantphos (168 mg, 291 μιηοΐ), the reaction mixture was allowed to stir overnight at 65°C. After cooling to rt, the reaction mixture was filtered through celite, rinsing with dichloromethane and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 95:5 to 80:20 to deliver 542.5 mg (91 % purity, 50 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.65 min; MS (ESIpos): m/z = 690 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.113 (1.00), 1.119 (1.01), 1.127 (0.48), 1.235 (0.49), 1.243 (1.06), 1.249 (0.87), 1.387 (0.55), 1.409 (2.19), 1.434 (16.00), 2.191 (3.99), 2.449 (1.19), 3.195 (0.99), 3.205 (1.37), 3.215 (1.09), 3.520 (1.12), 7.216 (0.69), 7.232 (0.71), 7.355 (0.56), 7.361 (0.56), 7.373 (0.60), 7.378 (0.62), 7.665 (0.41), 7.668 (0.45), 7.683 (0.40), 7.756 (0.90), 7.782 (0.87), 8.307 (2.06), 8.566 (1.01), 8.571 (1.06), 10.643 (0.89).

Example 47

tert-butyl [(3S)-l -{6-fluoro-3-[3- {[l -(morpholin-4-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (50.0 mg, 87.5 μηιοΐ), tert-butyl (3S)-pyrrolidin-3- ylcarbamate (29.3 mg, 158 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.01 mg, 8.75 μιηοΐ), cBRIDP (6.17 mg, 17.5 μιηοΐ) and cesium carbonate (85.5 mg, 263 μιηοΐ) was suspended in 1,4-dioxane (880 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 95°C overnight. After addition of more tert-butyl (3S)-pyrrolidin-3-ylcarbamate (26.1 mg, 140 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.01 mg, 8.75 μιηοΐ) and cBRIDP (6.17 mg, 17.5 μιηοΐ), the reaction mixture was allowed to stir overnight at 95°C. After cooling to rt, the reaction mixture was filtered through celite, rinsing with a mixture of dichloromethane/methanol 10: 1 and the filtrate was evaporated under reduced pressure. The residue was purified by two consecutive preparative RP-HPLC (125x30mm) with acetonitrile/water (neutral conditions) to deliver 18.0 mg (99 % purity, 30 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.20 min; MS (ESIpos): m/z = 677 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.78), 1.108 (0.64), 1.120 (1.76), 1.128 (1.87), 1.138 (0.86), 1.235 (0.44), 1.264 (0.85), 1.274 (1.89), 1.281 (1.60), 1.293 (0.64), 1.400 (16.00), 1.910 (0.44), 2.119 (0.44), 2.461 (2.59), 3.372 (0.55), 3.398 (0.53), 3.547 (0.46), 3.633 (0.48), 3.652 (0.48), 3.699 (2.56), 3.750 (0.52), 6.739 (1.11), 6.759 (1.14), 7.235 (0.43), 7.356 (0.99), 7.362 (0.98), 7.377 (1.07), 7.384 (1.08), 7.640 (1.81), 7.654 (0.92), 7.676 (2.39), 8.225 (3.84), 8.490 (2.02), 8.497 (1.99), 10.602 (1.86).

Example 48

tert-butyl 4- {6-fluoro-3-[3- {[l-(morpholin-4-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate

A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (50.0 mg, 87.5 μιηοΐ), tert-butyl piperazine-l-carboxylate (29.3 mg, 158 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.01 mg, 8.75 μιηοΐ), cBRIDP (6.17 mg, 17.5 μιηοΐ) and cesium carbonate (85.5 mg, 263 μιηοΐ) was suspended in 1,4-dioxane (880 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 95°C overnight followed by 3 d of stirring at rt. The reaction mixture was filtered through celite, rinsing with a mixture of dichloromethane/methanol 10: 1 and the filtrate was evaporated under reduced pressure. The residue was purified by two consecutive preparative RP-HPLC (125x30mm) with acetonitrile/water (neutral conditions) to deliver 9.60 mg (95 % purity, 15 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.27 min; MS (ESIpos): m/z = 677 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.87), 0.008 (0.50), 1.120 (0.94), 1.127 (0.96), 1.138 (0.44), 1.265 (0.50), 1.275 (1.07), 1.282 (0.82), 1.333 (0.45), 1.435 (16.00), 2.462 (1.71), 2.473 (1.51), 2.519 (0.77), 2.521 (0.71), 2.524 (0.80), 3.194 (0.97), 3.206 (1.32), 3.218 (1.04), 3.521 (1.18), 3.699 (1.35), 7.218 (0.69), 7.238 (0.70), 7.369 (0.57), 7.376 (0.55), 7.391 (0.59), 7.398 (0.60), 7.672 (0.43), 7.676 (0.44), 7.694 (0.42), 7.758 (0.86), 7.790 (0.82), 8.311 (1.89), 8.515 (1.00), 8.521 (0.97), 10.611 (0.94).

Example 49

tert-butyl [(3R)-l- {6-fluoro-3-[3- {[l -(morpholin-4-yl)cyclopropane-l -carbonyl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p yrrolidin-3-yl]carbamate

A mixture of N-[5-(7-bromo-6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(trifluor omethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane-l-carboxamide (50.0 mg, 100 % purity, 87.5 μιηοΐ), tert-butyl (3R)- pyrrolidin-3-ylcarbamate (29.3 mg, 158 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.01 mg, 8.75 μιηοΐ), cBRIDP (6.17 mg, 17.5 μιηοΐ) and cesium carbonate (85.5 mg, 263 μιηοΐ) was suspended in 1,4- dioxane (880 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 95°C overnight followed by 3 d of stirring at rt. The reaction mixture was filtered through celite, rinsing with a mixture of dichloromethane/methanol 10:1 and the filtrate was evaporated under reduced pressure. The residue was purified by two consecutive preparative RP-HPLC (125x30mm) with acetonitrile/water (neutral conditions) to deliver 13.9 mg (99 % purity, 23 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.28 min; MS (ESIpos): m/z = 677 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 1.108 (0.57), 1.120 (1.64), 1.128 (1.77), 1.138 (0.82), 1.264 (0.79), 1.274 (1.80), 1.281 (1.53), 1.293 (0.64), 1.400 (16.00), 1.894 (0.42), 1.909 (0.45), 2.118 (0.44), 2.461 (2.54), 3.373 (0.51), 3.547 (0.44), 3.631 (0.47), 3.698 (2.51), 6.740 (1.13), 6.760 (1.16), 7.237 (0.44), 7.356 (0.96), 7.363 (0.96), 7.378 (1.07), 7.384 (1.04), 7.641 (1.82), 7.658 (0.87), 7.676 (2.40), 8.226 (3.70), 8.490 (1.92), 8.497 (1.88), 10.602 (1.80).

Example 50

tert-butyl [(3R)- 1 - {3-[4-(difluoromethoxy)-3 - { [ 1 -(4-methylpiperazin-l -yl)cyclopropane- 1 - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyrrolidin-3 -yljcarbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (30.0 mg, 54.7 μιηοΐ), tert-butyl (3R)-pyrrolidin-3- ylcarbamate (11.2 mg, 60.2 μιηοΐ), tris(dibenzylidenacetone)dipalladium (5.01 mg, 5.47 μιηοΐ), Xantphos (6.33 mg, 10.9 μιηοΐ) and cesium carbonate (53.5 mg, 164 μιηοΐ) was suspended in 1,4- dioxane (550 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 11.0 mg (99 % purity, 31 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.38 min; MS (ESIpos): m/z = 654 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (1.35), 0.008 (1.18), 1.085 (0.65), 1.098 (1.78), 1.105 (2.03), 1.115 (0.98), 1.202 (0.96), 1.212 (2.06), 1.219 (1.72), 1.233 (1.07), 1.402 (16.00), 1.935 (0.48), 1.949 (0.52), 2.165 (0.47), 2.183 (0.66), 2.217 (3.33), 2.454 (2.12), 3.184 (0.57), 3.196 (0.66), 3.210 (0.71), 3.222 (0.70), 3.370 (0.43), 3.394 (0.60), 3.410 (0.65), 3.504 (0.64), 3.528 (0.49), 3.585 (0.53), 3.602 (0.69), 3.611 (0.60), 3.628 (0.51), 4.179 (0.44), 6.574 (1.61), 6.579 (1.68), 6.808 (0.88), 6.814 (0.86), 6.831 (0.91), 6.836 (0.90), 7.245 (0.53), 7.261 (1.46), 7.267 (1.26), 7.283 (1.22), 7.290 (2.02), 7.444 (1.63), 7.466 (1.35), 7.474 (2.04), 7.658 (0.87), 7.930 (1.93), 7.952 (1.76), 8.162 (4.40), 8.469 (1.57), 8.476 (1.59), 10.665 (1.05).

Example 51

l-(morpholin-4-yl)-N- {5-[7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-oxoquinazolin-3(4 H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide

Three parallel batches were prepared under the same conditions and combined for purification. A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 90.4 μιηοΐ), 2-oxa-6-azaspiro[3.3]heptane ethanedioate (2:1) (39.1 mg, 136 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.27 mg, 9.04 μιηοΐ), cBRIDP (6.37 mg, 18.1 μιηοΐ) and cesium carbonate (118 mg, 361 μιηοΐ) was suspended in 1,4-dioxane (900 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C overnight. After cooling to rt, the 3 reaction mixtures were combined and filtered through celite, rinsing with a dichloromethane/methanol mixture and the filtrate was evaporated under reduced pressure. The residue was purified a by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 98:2 to 90: 10. The material obtained was then purified by preparative RP-HPLC 125x40mm with acetonitrile/water (0.1% formic acid) to deliver 75.0 mg (99 % purity, 48 % corrected yield) of the title compound. LC-MS (Method 6): R _t = 1.85 min; MS (ESIpos): m/z = 572 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: 1.104 (1.08), 1.116 (3.16), 1.123 (3.37), 1.133 (1.52), 1.261 (1.54), 1.271 (3.46), 1.278 (2.98), 1.291 (1.11), 2.325 (0.43), 2.670 (0.44), 3.696 (5.18), 4.188 (16.00), 4.751 (15.68), 6.489 (2.66), 6.650 (1.42), 6.672 (1.46), 7.345 (1.31), 7.352 (1.26), 7.367 (1.51), 7.373 (1.46), 7.647 (1.52), 7.669 (1.30), 7.941 (2.33), 7.962 (2.24), 8.215 (4.57), 8.478 (2.40), 8.484 (2.29), 10.598 (3.08).

Example 52

tert-butyl 4- {3-[4-(difluoromethoxy)-3- {[l -(4-methylpiperazin-l-yl)cyclopropane-l- carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} piperazine- 1 -carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(difluoromethoxy)p henyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (50.0 mg, 91.2 μιηοΐ), tert-butyl piperazine-1- carboxylate (18.7 mg, 100 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.35 mg, 9.12 μιηοΐ), Xantphos (10.6 mg, 18.2 μιηοΐ) and cesium carbonate (89.1 mg, 274 μιηοΐ) was suspended in 1,4-dioxane (1.0 ml) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C overnight. After cooling to rt, the reaction mixture was filtered through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85: 15 (+ 0.2 % ammonia). The material obtained was then purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 22.0 mg (99 % purity, 37 % yield) of the title compound.

LC-MS (Method 1): R _t = 0.80 min; MS (ESIpos): m/z = 654 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (0.90), 1.095 (0.88), 1.103 (0.94), 1.113 (0.44), 1.203 (0.51), 1.212 (0.99), 1.220 (0.78), 1.233 (0.54), 1.433 (16.00), 2.202 (3.48), 2.519 (0.82), 2.524 (0.86), 3.417 (1.37), 3.425 (1.25), 3.431 (1.18), 3.478 (1.25), 3.485 (1.22), 3.493 (1.20), 7.014 (0.79), 7.020 (0.78), 7.222 (0.42), 7.245 (0.44), 7.251 (0.42), 7.265 (0.54), 7.272 (0.51), 7.287 (0.60), 7.294 (0.72), 7.453 (0.77), 7.474 (0.68), 7.480 (1.04), 7.664 (0.44), 7.965 (0.98), 7.987 (0.85), 8.208 (2.19), 8.486 (1.01), 8.492 (0.97), 10.683 (0.85). Example 53

tert-butyl 4- {3 -[3- {[1 -(6-oxa-3-azabicyclo[3.1.l]heptan-3-yl)cyclopropane-l-carbon yl]amino}-4- (trifluoromethoxy)phenyl]-4-oxo-3,4-dihydroquinazolin-7-yl}p iperazine-l -carboxylate

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), tert-butyl piperazine-l -carboxylate (13.0 mg, 69.8 μmol), tris(dibenzylidenacetone)dipalladium (5.81 mg, 6.35 μmol), Xantphos (7.35 mg, 12.7 μιηοΐ) and cesium carbonate (62.1 mg, 190 μιηοΐ) was suspended in 1 ,4-dioxane (640 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 70°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to deliver 13.4 mg (99 % purity, 31 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.19 min; MS (ESIpos): m/z = 671 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.262 (1.04), 1.299 (0.99), 1.434 (16.00), 2.523 (0.62), 2.924 (0.44), 2.951 (0.91), 2.994 (1.16), 3.021 (0.55), 3.422 (1.23), 3.429 (1.16), 3.436 (1.23), 3.480 (1.16), 3.494 (1.17), 4.516 (0.86), 4.532 (0.86), 7.021 (0.74), 7.027 (0.79), 7.374 (0.40), 7.390 (0.45), 7.396 (0.47), 7.971 (0.98), 7.993 (0.88), 8.247 (1.73), 8.430 (0.78), 8.437 (0.80), 9.968 (0.54).

Example 54

tert-butyl [(3R)-l- {3-[4-(methoxymethyl)-3- {[l-(4-methylpiperazin-l -yl)cyclopropane-l - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} pyrrolidin-3 -yl]carbamate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phe nyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (50.0 mg, 95.0 μιηοΐ), tert-butyl (3R)-pyrrolidin-3- ylcarbamate (31.8 mg, 171 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.35 mg, 4.75 μmol), Xantphos (5.50 mg, 9.50 μιηοΐ) and cesium carbonate (92.8 mg, 285 μιηοΐ) was suspended in 1,4- dioxane (950 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 24 h. After a further addition of tert-butyl (3R)-pyrrolidin-3-ylcarbamate (31.8 mg, 171 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.35 mg, 4.75 μιηοΐ) and Xantphos (5.50 mg, 9.50 μιηοΐ), the reaction mixture was allowed to stir for another 18 h. After cooling to rt, the reaction mixture was partitioned in dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90: 10 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions) to deliver 4.50 mg (99 % purity, 7 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.33 min; MS (ESIneg): m/z = 630 [M-H] ^"

Ή-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.023 (6.58), 0.840 (0.70), 0.854 (1.43), 0.867 (0.62), 1.073 (2.18), 1.079 (2.38), 1.087 (1.20), 1.175 (2.39), 1.180 (2.09), 1.190 (1.02), 1.234 (16.00), 1.402 (14.01), 1.936 (0.54), 1.949 (0.57), 1.962 (0.42), 2.171 (0.55), 2.184 (0.82), 2.202 (8.53), 3.190 (0.67), 3.199 (0.79), 3.210 (0.84), 3.220 (0.83), 3.370 (12.84), 3.392 (1.04), 3.409 (0.92), 3.494 (0.41), 3.508 (0.80), 3.526 (0.60), 3.590 (0.57), 3.603 (0.71), 3.610 (0.66), 3.623 (0.52), 4.182 (0.50), 4.609 (4.62), 6.579 (1.65), 6.812 (0.86), 6.816 (0.87), 6.830 (0.92), 6.834 (0.89), 7.190 (1.02), 7.194 (1.06), 7.206 (1.10), 7.210 (1.14), 7.247 (0.62), 7.259 (0.61), 7.487 (1.63), 7.503 (1.48), 7.935 (1.70), 7.952 (1.60), 8.160 (3.84), 8.273 (1.98), 8.277 (2.06), 10.605 (1.83).

Example 55

tert-butyl 4- {3 - [4-(methoxymethyl) -3 - { [ 1 -(4-methylpiperazin- 1 -yl)cyclopropane- 1 - carbonyl] amino } phenyl] -4-oxo-3 ,4-dihydroquinazolin-7-yl} piperazine- 1 -carboxylate

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(methoxymethyl)phe nyl]-l-(4- methylpiperazin-l -yl)cyclopropane-l -carboxamide (50.0 mg, 95.0 μιηοΐ), tert-butyl piperazine-1- carboxylate (31.8 mg, 171 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.35 mg, 4.75 μmol), Xantphos (5.50 mg, 9.50 μιηοΐ) and cesium carbonate (92.8 mg, 285 μιηοΐ) was suspended in 1,4-dioxane (950 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 80°C for 24 h. After a further addition of tert-butyl piperazine-l -carboxylate (31.8 mg, 171 μιηοΐ), tris(dibenzylidenacetone)dipalladium (4.35 mg, 4.75 μιηοΐ) and Xantphos (5.50 mg, 9.50 μιηοΐ), the reaction mixture was allowed to stir for another 18 h. After cooling to rt, the reaction mixture was partitioned in dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography over silica gel eluting with a gradient of dichloromethane/methanol from 99: 1 to 90:10 followed by a preparative RP-HPLC 125x30mm with acetonitrile/water (neutral conditions). The same purification steps (over silica gel followed by preparative RP-HPLC) were repeated one more time in the same conditions to deliver 7.70 mg (99 % purity, 13 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.40 min; MS (ESIpos): m/z = 632 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm]: 1.073 (0.86), 1.079 (0.94), 1.087 (0.46), 1.167 (0.44), 1.175 (0.97), 1.181 (0.76), 1.434 (16.00), 2.202 (4.06), 2.433 (0.79), 2.475 (0.69), 3.371 (7.61), 3.408 (0.72), 3.417 (1.23), 3.423 (1.07), 3.429 (1.21), 3.482 (1.07), 3.492 (1.08), 4.611 (2.12), 7.016 (0.77), 7.021 (0.77), 7.196 (0.55), 7.200 (0.53), 7.212 (0.56), 7.216 (0.58), 7.225 (0.41), 7.244 (0.41), 7.494 (0.82), 7.510 (0.74), 7.969 (1.03), 7.987 (0.90), 8.205 (2.44), 8.283 (1.01), 8.287 (0.98), 10.609 (0.77).

Example 56

N-[5- {7-[3-methoxypyrrolidin-l -yl]-4-oxoquinazolin-3(4H)-yl}-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane- 1 -carboxamide (racemate)

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 98 % purity, 88.6 μιηοΐ), 3-methoxypyrrolidine (16.1 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in 1,4-dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 23.7 mg (99 % purity, 46 % yield) of the title compound.

LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m/z = 574 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : 1.122 (0.78), 1.128 (0.80), 1.272 (0.82), 1.279 (0.68), 2.462 (0.95), 2.470 (0.71), 3.292 (6.80), 3.310 (16.00), 3.691 (0.67), 3.699 (0.93), 6.621 (0.67), 6.625 (0.67), 7.357 (0.51), 7.363 (0.49), 7.375 (0.52), 7.380 (0.53), 7.940 (0.92), 7.958 (0.83), 8.199 (2.09), 8.487 (0.91), 8.492 (0.89), 10.597 (0.72).

Example 57

1 -(morpholin-4-yl)-N- {5-[4-oxo-7-(pyrrolidin-l -yl)quinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 98 % purity, 88.6 μιηοΐ), pyrrolidine (13 μΐ, 160 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μηιοΐ), Xantphos (10.2 mg, 17.7 μηιοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in 1,4-dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 7.70 mg (99 % purity, 16 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.16 min; MS (ESIpos): m/z = 544 [M+H] ⁺

Ή- MR (500 MHz, DMSO-d6) δ [ppm] : -0.007 (2.69), 0.007 (1.91), 1.112 (2.27), 1.122 (6.15), 1.128 (6.30), 1.136 (2.91), 1.265 (2.82), 1.273 (6.47), 1.279 (5.39), 1.289 (2.26), 1.994 (4.42), 2.001 (5.28), 2.008 (11.92), 2.013 (5.04), 2.021 (4.34), 2.032 (0.44), 2.362 (0.42), 2.462 (7.47), 2.470 (5.70), 2.518 (0.62), 2.522 (0.45), 2.635 (0.40), 3.373 (4.47), 3.386 (11.16), 3.399 (4.06), 3.691 (5.21), 3.699 (7.19), 3.707 (5.07), 6.605 (5.21), 6.610 (5.21), 6.833 (2.91), 6.838 (2.69), 6.851 (2.93), 6.856 (2.77), 7.353 (3.97), 7.358 (3.86), 7.371 (4.08), 7.376 (4.19), 7.646 (2.69), 7.649 (2.68), 7.660 (1.14), 7.664 (2.47), 7.667 (2.19), 7.935 (7.22), 7.952 (6.58), 8.192 (16.00), 8.484 (7.08), 8.489 (6.96), 10.597 (5.45).

Example 58

l-(morpholin-4-yl)-N- {5-[7-(morpholin-4-yl)-4-oxoquinazolin-3(4H)-yl]-2- (trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 98 % purity, 88.6 μιηοΐ), morpholine (14 μΐ, 160 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in 1,4-dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 21.1 mg (99 % purity, 43 % yield) of the title compound. LC-MS (Method 6): R _t = 1.92 min; MS (ESIpos): m/z = 560 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.60), 0.008 (4.82), 0.069 (0.60), 0.146 (0.52), 1.109 (2.85), 1.121 (7.70), 1.128 (8.14), 1.139 (3.77), 1.223 (0.43), 1.265 (3.79), 1.275 (7.98), 1.282 (6.89), 1.294 (2.65), 2.327 (1.31), 2.366 (0.67), 2.464 (12.72), 2.670 (1.41), 2.710 (0.78), 3.361 (11.60), 3.373 (16.00), 3.385 (12.36), 3.700 (12.44), 3.753 (12.67), 3.765 (15.83), 3.777 (11.07), 7.028 (7.03), 7.033 (7.21), 7.243 (3.63), 7.249 (3.39), 7.266 (3.83), 7.272 (3.63), 7.362 (3.10), 7.368 (3.26), 7.384 (3.75), 7.390 (3.69), 7.660 (3.36), 7.679 (2.98), 7.978 (7.98), 8.000 (7.32), 8.250 (11.07), 8.497 (5.91), 8.503 (5.80), 10.605 (7.84).

Example 59

N-[5- {7-[3-hydroxypyrrolidin-l-yl]-4-oxoquinazolin-3(4H)-yl} -2-(trifluoromethoxy)phenyl]-l- (morpholin-4-yl)cyclopropane- 1 -carboxamide (racemate)

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 98 % purity, 88.6 μιηοΐ), pyrrolidin-3-ol (13.9 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in 1,4-dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 23.3 mg (99 % purity, 47 % yield) of the title compound.

LC-MS (Method 6): R _t = 1.69 min; MS (ESIpos): m/z = 560 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.91), 0.008 (2.43), 0.069 (0.65), 1.109 (3.03), 1.121 (8.55), 1.129 (9.41), 1.139 (4.49), 1.222 (0.45), 1.263 (4.00), 1.273 (8.99), 1.280 (7.59), 1.293 (3.03), 1.938 (1.28), 1.962 (1.88), 1.971 (2.08), 2.039 (0.90), 2.061 (2.12), 2.072 (2.52), 2.083 (1.73), 2.093 (2.27), 2.104 (1.41), 2.126 (0.60), 2.327 (1.03), 2.366 (0.61), 2.463 (13.41), 2.670 (1.05), 2.709 (0.65), 3.230 (3.62), 3.257 (4.33), 3.428 (1.05), 3.442 (3.48), 3.451 (4.92), 3.465 (5.09), 3.472 (5.08), 3.488 (2.91), 3.514 (3.72), 3.526 (4.01), 3.541 (3.27), 3.553 (2.87), 3.700 (13.29), 4.450 (3.65), 5.086 (0.80), 6.590 (8.13), 6.595 (8.45), 6.818 (4.20), 6.823 (4.06), 6.840 (4.32), 6.846 (4.25), 7.355 (3.93), 7.361 (3.96), 7.377 (4.47), 7.383 (4.68), 7.465 (0.44), 7.648 (3.93), 7.667 (3.49), 7.934 (10.41), 7.956 (9.54), 8.194 (16.00), 8.484 (7.93), 8.490 (8.01), 8.561 (0.84), 10.598 (8.96). Example 60

N-[5- {7-[3-methoxypiperidin-l -yl]-4-oxoquinazolin-3(4H)-yl}-2-(trifluoromethoxy)phenyl]-l - (morpholin-4-yl)cyclopropane- 1 -carboxamide (racemate)

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 98 % purity, 88.6 μιηοΐ), 3-methoxypiperidine (18.4 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in 1,4-dioxane (880 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 16.9 mg (99 % purity, 32 % yield) of the title compound.

LC-MS (Method 6): R _t = 2.07 min; MS (ESIpos): m/z = 588 [M+H] ⁺

Ή- MR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.22), 0.008 (2.27), 1.110 (3.13), 1.122 (9.12), 1.130 (9.79), 1.140 (5.09), 1.158 (0.51), 1.182 (0.41), 1.223 (0.44), 1.264 (4.12), 1.274 (9.49), 1.281 (8.16), 1.294 (3.20), 1.466 (0.59), 1.491 (3.01), 1.513 (5.37), 1.533 (3.91), 1.557 (0.93), 1.775 (2.11), 1.781 (2.15), 1.789 (1.96), 1.805 (0.98), 1.946 (1.35), 1.970 (2.49), 1.995 (1.04), 2.327 (0.75), 2.366 (0.46), 2.463 (13.58), 2.670 (0.97), 2.710 (0.59), 2.782 (0.96), 3.127 (2.57), 3.147 (3.25), 3.159 (3.02), 3.179 (4.51), 3.199 (2.19), 3.208 (1.79), 3.222 (1.63), 3.340 (3.38), 3.483 (0.42), 3.611 (2.04), 3.644 (1.86), 3.700 (13.73), 3.801 (2.83), 3.809 (2.87), 3.834 (2.72), 6.982 (7.79), 6.988 (8.33), 7.223 (3.87), 7.229 (3.83), 7.246 (4.23), 7.252 (4.16), 7.349 (4.05), 7.356 (4.12), 7.371 (4.65), 7.377 (4.76), 7.655 (4.03), 7.674 (3.47), 7.924 (9.55), 7.947 (8.67), 8.217 (16.00), 8.489 (7.88), 8.495 (8.00), 8.563 (1.39), 10.602 (9.57). Example 61

N-{5-[7-(4-hydroxy-4-methylpiperidin-l-yl)-4-oxoquinaz

(morpholin-4-yl)cyclopropane- 1 -carboxamide

A mixture of N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy) phenyl]-l -(morpholin-4- yl)cyclopropane-l -carboxamide (50.0 mg, 98 % purity, 88.6 μιηοΐ), 4-methylpiperidin-4-ol (18.4 mg, 159 μιηοΐ), tris(dibenzylidenacetone)dipalladium (8.11 mg, 8.86 μιηοΐ), Xantphos (10.2 mg, 17.7 μιηοΐ) and cesium carbonate (86.6 mg, 266 μιηοΐ) was suspended in 1,4-dioxane (890 μΐ) and degassed by passing an argon stream through it for 5 min. The reaction mixture was then heated to 100°C overnight. After cooling to rt, 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 purified by preparative RP-HPLC 125x30mm with acetonitrile/water (0.2% ammonia) to deliver 12.5 mg (96 % purity, 23 % yield) of the title compound.

LC-MS (Method 1): R _t = 0.99 min; MS (ESIpos): m/z = 588 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.008 (2.31), 0.008 (2.13), 1.110 (1.22), 1.122 (3.43), 1.130 (3.79), 1.140 (1.88), 1.159 (16.00), 1.263 (1.58), 1.273 (3.59), 1.280 (3.08), 1.293 (1.20), 1.509 (0.42), 1.532 (1.78), 1.557 (4.93), 1.590 (0.54), 2.462 (5.22), 2.472 (4.02), 3.327 (1.55), 3.350 (1.94), 3.360 (1.31), 3.372 (1.10), 3.383 (1.02), 3.631 (2.04), 3.654 (1.09), 3.664 (1.83), 3.700 (5.18), 4.408 (2.58), 6.982 (2.79), 6.988 (2.91), 7.210 (1.41), 7.216 (1.38), 7.233 (1.49), 7.239 (1.43), 7.345 (1.59), 7.352 (1.59), 7.367 (1.79), 7.374 (1.82), 7.653 (1.52), 7.672 (1.32), 7.922 (3.18), 7.945 (2.91), 8.209 (6.44), 8.486 (3.20), 8.493 (3.18), 10.601 (3.40).

Example 62

l-(4-methylpiperazin-l-yl)-N-{5-[7-(2-oxaspiro[3.3]heptan -6-yl)-4-oxoquinazolin

(trifluoromethoxy)phenyl} cyclopropane- 1 -carboxamide O

N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluorometho xy)phenyl] - 1 -(4-methylpiperazin- 1 - yl)cyclopropane-l -carboxamide (147 mg, 260 μηιοΐ) and Iridium(l+), [4,4'-bis(l,l-dimethylethyl)-2,2'- bipyridine-KNl ,KN ]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-KN]phen yl-KC]-, (OC-6-33)-, hexafluorophosphate(l-) (1 : 1) (CAS 870987-63-6) (8.76 mg, 7.80 μιηοΐ) were placed under argon in a 10 ml vial equipped with a cooling finger. 4,4'-Di-tert-butyl-2,2'-bipyridine (3.49 mg, 13.0 μιηοΐ) and (l,2-Dimethoxyethane)nickel dichloride (CAS 29046-78-4) (2.86 mg, 13.0 μιηοΐ) were charged under argon in a vial and dissolved in degassed 1 ,2-dimethoxyethane (5.2 ml). This mixture was stirred at rt for 10 min under argon before being added to the vial containing the iridium catalyst. To this suspension were then subsequently added 6-bromo-2-oxaspiro[3.3]heptane (87 μΐ, 780 μιηοΐ), 1,1,1,3,3,3- hexamethyl-2-(trimethylsilyl)trisilane (88 μΐ, 290 μιηοΐ), 2,6-dimethylpyridine (120 μΐ, 1.0 mmol). An argon stream was passed through the suspension for 5 min, the cooling finger was placed in the reaction and the reaction mixture was stirred at rt for 16 h while irradiated with three 34W blue LED lamps. The solvents were evaporated under reduced pressure and the crude material obtained was then purified by preparative RP-HPLC 125x40mm with acetonitrile/water (neutral conditions) followed by preparative RP-HPLC 125x30mm with acetonitrile/water (0.1% ammonia) to provide 11.2 mg (99 % purity, 7 % yield) of the title product.

LC-MS (Method 6): R _t = 1.31 min; MS (ESIpos): m/z = 584 [M+H] ⁺

Ή-NMR (400 MHz, DMSO-d6) δ [ppm] : -0.150 (1.37), -0.008 (11.08), 0.008 (10.63), 0.146 (1.25), 1.099 (1.21), 1.111 (3.67), 1.119 (4.13), 1.129 (2.08), 1.234 (1.88), 1.244 (4.17), 1.251 (3.37), 1.264 (1.46), 2.150 (0.58), 2.192 (16.00), 2.227 (0.75), 2.327 (3.29), 2.351 (3.58), 2.358 (3.79), 2.366 (2.67), 2.375 (2.00), 2.382 (2.83), 2.453 (5.83), 2.670 (3.46), 2.691 (2.83), 2.710 (2.17), 2.722 (2.08), 3.473 (0.46), 3.496 (1.33), 3.517 (1.92), 3.539 (1.21), 4.512 (12.92), 4.729 (12.92), 7.370 (2.08), 7.376 (2.12), 7.392 (2.37), 7.398 (2.46), 7.448 (2.12), 7.469 (2.37), 7.532 (4.13), 7.676 (1.88), 7.694 (1.58), 8.104 (4.00), 8.125 (3.63), 8.342 (8.67), 8.576 (4.17), 8.583 (4.04), 10.650 (3.71). 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-l 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% C0 ₂ 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% C0 ₂ 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 Ca ²⁺ 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□ -catenin mutant Wnt signaling cascade: HCT116 TOP/FOP Assay

In order to discover and characterize small molecules which inhibit the constitutively active _ -catenin mutant Wnt pathway, a cellular reporter assay was employed. The corresponding assay cell was generated by transfection of the mammalian cell line HCT116 (ATCC, #CCL-247) with the Super TopFlash vector (Morin, Science 275, 1997, 1787-1790; Molenaar et al., Cell 86 (3), 1996, 391 -399). The HCTl 16 cell line is cultivated at 37°C and 5% C0 ₂ in DMEM/F12 (Life Technologies, #11320- 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, HCTl 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) HCTl 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 Ca ²⁺ 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, 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.

Table 2: Assay results on inhibitory activity on the D-catenin mutant and wildtype Wnt signaling cascade

HEK293 HCT116 HEK293 HCT116

Example Example

TOPFlash ICso TOPFlash TOPFlash ICso TOPFlash No No

[mol/L] IC50 (mol/L) [mol/L] IC50 (mol/L)

Example 1 2.90 E-8 1.90 E-8 Example 12 9.50 E-8 4.40 E-8

Example 2 1.14 E-7 5.85 E-8 Example 13 4.35 E-8 1.22 E-8

Example 3 1.25 E-7 2.10 E-8 Example 14 4.70 E-8 2.90 E-8

Example 4 2.00 E-8 1.00 E-8 Example 15 1.45 E-7 4.70 E-8

Example 5 6.10 E-8 3.55 E-8 Example 16 6.10 E-8 2.40 E-8

Example 6 5.70 E-8 1.55 E-8 Example 17 1.04 E-7 1.40 E-8

Example 7 1.30 E-7 7.50 E-8 Example 18 7.50 E-8 1.75 E-8

Example 8 9.00 E-8 1.85 E-8 Example 19 2.45 E-8 1.85 E-8

Example 9 1.35 E-7 3.65 E-8 Example 20 2.95 E-8 1.45 E-8

Example 10 1.60 E-7 5.30 E-8 Example 21 7.40 E-8 1.30 E-8

Example 11 7.50 E-8 7.25 E-8 Example 22 5.05 E-8 1.05 E-8 HEK293 HCT116 HEK293 HCT116

Example Example

TOPFlash ICso TOPFlash TOPFlash ICso TOPFlash No No

[mol/L] IC50 (mol/L) [mol/L] IC50 (mol/L)

Example 23 1.85 E-7 3.60 E-8 Example 35 7.35 E-7 6.15 E-8

Example 24 1.40 E-7 1.85 E-7 Example 36 1.90 E-7 5.45 E-8

Example 25 3.45 E-8 1.45 E-8 Example 37 2.40 E-7 5.20 E-8

Example 26 5.65 E-8 1.15 E-8 Example 38 4.60 E-8 2.00 E-8

Example 27 9.45 E-8 1.45 E-8 Example 39 7.80 E-8 2.15 E-8

Example 28 3.05 E-7 3.60 E-8 Example 40 9.40 E-8 1.95 E-8

Example 29 1.85 E-8 1.02 E-8 Example 41 3.75 E-8 1.65 E-8

Example 30 3.60 E-8 3.30 E-8 Example 42 9.40 E-8 5.95 E-8

Example 31 4.05 E-8 1.80 E-8 Example 43 2.40 E-7 6.95 E-8

Example 32 2.65 E-8 2.75 E-8 Example 44 2.25 E-7 5.18 E-8

Example 33 4.70 E-8 4.25 E-8 Example 45 4.53 E-8 4.40 E-8

Example 34 2.95 E-8 1.80 E-8 Example 46 3.33 E-8 2.90 E-8 HEK293 HCT116 HEK293 HCT116

Example Example

TOPFlash IC ₅₀ TOPFlash TOPFlash IC ₅₀ TOPFlash No No

[mol/L] IC50 (mol/L) [mol/L] IC50 (mol/L)

Example 47 4.83 E-8 1.38 E-8 Example 55 1.16 E-7 3.90 E-8

Example 48 8.30 E-8 5.50 E-8 Example 56 3.00 E-7 7.55 E-8

Example 49 6.60 E-8 1.25 E-8 Example 57 2.75 E-7 8.55 E-8

Example 50 8.30 E-8 3.10 E-8 Example 58 2.83 E-7 8.35 E-8

Example 51 2.70 E-7 3.80 E-7 Example 59 5.48 E-7 5.80 E-8

Example 52 1.20 E-7 2.65 E-8 Example 60 5.53 E-7 4.58 E-8

Example 53 4.83 E-8 9.68 E-9 Example 61 3.15 E-7 4.98 E-8

Example 54 9.65 E-7 7.25 E-8 Example 62 1.95 E-8 3.00 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.