New prop-2-ynamide derivatives

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A, p, R1-R3 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

[0001]F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P38775 NEW PROP-2-YNAMIDE DERIVATIVES The present invention relates to compounds that are selective inhibitors of EGFR exon20 bearing mutants, their manufacture, pharmaceutical compositions containing it and their use as therapeutically active substances. The invention relates in particular to a compound of formula (I) wherein A is -O- or -NR1’-; R1 is alkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl; R1’is hydrogen or alkyl; or R1and R1’, together with the -N- atom to which they are attached, form heterocycloalkyl optionally substituted with R4; R2 and R2’ are both independently selected from aryl and cycloalkyl, wherein aryl and cycloalkyl are at each instance optionally substituted with R5; R3 is hydrogen or alkyl; R4 is aryl, heteroaryl, heterocycloalkyl, cyanoaryl or haloaryl; R5is alkoxy, halo or haloalkyl; and, p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. The HER family receptor tyrosine kinases are mediators of cell growth, differentiation and survival. The receptor family includes four distinct members, i.e. epidermal growth factor receptor (EGFR, ErbBl, or HER1) HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Upon ligand binding the receptors form homo and heterodimers and subsequent activation of the intrinsic tyrosine kinase activity leads to receptor auto-phosphorylation and the activation of downstream signaling molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signalling network. Nature Review Mol Cell Biol. 2001 Feb;2(2): 127-37). De-regulation of EGFR by overexpression or mutation has been implicated in many types of human cancer including colorectal, pancreatic, gliomas, head and neck and lung cancer, in particular non-small cell lung cancer (NSCLC) and several EGFR targeting agents have been developed over the years (Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. The New England journal of medicine 358, 1160-1174). Erlotinib (Tarceva®), a reversible inhibitor of the EGFR tyrosine kinase was approved in numerous countries for the treatment of recurrent NSCLC. An impressive single agent activity of EGFR tyrosine kinase inhibitors is observed in a subset of NSCLC patients whose tumors harbor somatic kinase domain mutations, whereas clinical benefit in wild-type EGFR patients is greatly diminished (Paez, J. et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY 304, 1497-1500). The most common somatic mutations of EGFR are exon 19 deletions with delta 746-750 the most prevalent mutation and the exon 21 amino acid substitutions with L858R the most frequent mutation (Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3): 169-81). The FDA-approved inhibitors geftitinib, erlotinib and afatinib, targeting mutations in exons 18, 19, and 21, are effective in patients but the response is often not durable. Treatment resistance arises frequently, often due to the secondary T790M mutation within the ATP site of the receptor. Some developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C797S, that is the cysteine residue with which they form a key covalent bond (Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015)). C797S mutation was further reported by Wang to be a major mechanism for resistance to T790M-targeting EGFR inhibitors (Wang et al. EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M- positive non-small cell lung cancer, J Hematol Oncol. 2016; 9: 59). Additional mutations that cause resistance to Osimertinib are described by Yang, for example L718Q.( Yang et al, Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non–Small Cell Lung Cancer Patients, Clinical Cancer Research, DOI: 10.1158 / 1078-0432.CCR-17-2310) Lu et al.( Targeting EGFRL858R / T790Mand EGFRL858R / T790M / C797Sresistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018; 1-32) report in a review article on Targeting EGFRL858R / T790Mand EGFRL858R / T790M / C797Sresistance mutations in NSCLC treatment. As most available EGFR tyrosine kinase inhibitors target the ATP-site of the kinase, there is a need for new therapeutic agents that work differently, for example through targeting drug- resistant EGFR mutants. Recent studies suggest that purposefully targeting allosteric sites might lead to mutant-selective inhibitors (Jia et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129-132) On the other hand, small in-frame insertions of EGFR exon20 are resistant to all clinically-approved EGFR inhibitors at doses achievable in lung cancer patients and present an unmet medical need (Yasuda et al., 2013). Patients with EGFR exon20 insertions, such as V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH and V774_C775insHV, show particular low response rates to all currently approved EGFR-target therapies, with significantly reduced progression-free survival and overall survival rates (Chen et al., 2016). The current standard therapy for patients carrying an EGFR exon20 insertion is chemotherapy with limited efficacy and undesired side-effects. Accordingly, there is a high unmet medical need for the generation of selective molecules that specifically inhibit EGFR exon20 insertion mutants with selectivity over wild-type EGFR and thus provide novel therapeutic options for the affected patients. The compound of formula (I) as described herein, relates to potent inhibitors of mutant EGFR and in particular EGFR exon20 insertion mutations. The compounds of the present invention have the potential to complement current therapeutic options and to provide additional safety and efficacy benefits for the affected patients. The compounds of the present invention are designed to covalently bind the EGFR exon20 insertion mutations via a Cys residue, thus irreversibly inhibiting the EGFR activity of this variant. The term "alkyl", alone or in combination, denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms, in particular of 1 to 7 carbon atoms, more particular of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, or tert-butyl. Methyl, ethyl and iso-propyl are particular examples of “alkyl” in the compound of formula (I). The term “cycloalkyl”, alone or in combination, denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having two carbon atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two carbon atoms. Particular cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantanyl or spiro[4.5]decan- 10-yl. Particular examples of “cycloalkyl” are cyclopropyl, cyclobutyl and cyclohexyl. The term "heterocycloalkyl", alone or in combination, denotes a monovalent saturated or partly unsaturated mono-, bi- or tricyclic ring system of 4 to 12 ring atoms, in particular 5 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common. “Hetercycloylkyl” may comprise a carbonyl group, wherein the carbon of the carbonyl group is part of the ring system. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N- heterocycloalkyl). Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidinyl, 1-piperidyl, 4- piperidyl, 2-oxopyrrolidin-1-yl, piperazinyl, piperazin-1-yl, azetidinyl, azetidin-1-yl, 3- azaspiro[5.5]undecan-3-yl, azaspiro[4.5]decan-2-yl, 2-azaspiro[4.4]nonan-2-yl, [(1S,5R,7R)-4- oxo-3-oxa-9-azatricyclo[5.3.0.01,5]decan-9-yl], [3-oxo-piperazin-1-yl], (1,1-dioxo-1,2- thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl), (3-oxo-1,5,6,8- tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H- pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4- yl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-1-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2-oxa-5,8-diazaspiro[3.5]nonan-8-yl), 3- azabicyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5-yl), (2-azabicyclo[2.2.1]heptan-2-yl), 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]hexan-3-yl), (6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-1-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, (2-oxo-1-piperidyl), (2,3- dihydropyridazino[4,5-b][1,4]oxazin-8-yl), pyrrolidin-1-yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-1-piperidyl), 2-oxo-4- piperidyl, 5-oxo-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, (7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin- 6-yl] and [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]. Particular examples of “heterocycloalkyl” are azetidinyl, piperazinyl, piperidyl, azaspiro[5.5]undecan-3- yl, azaspiro[4.5]decan-2-yl and azaspiro[4.4]nonan-2-yl, more particular examples are azetidin1-yl, piperazin-1-yl, 1-piperidyl, 3-azaspiro[5.5]undecan-3-yl, 2-azaspiro[4.5]decan-2- yl and 2-azaspiro[4.4]nonan-2-yl. In one particular embodiment, heterocycloalkyl is “N- heterocycloalkyl”. The term “heteroaryl”, alone or in combination, signifies a monovalent aromatic mono -, bi- or tricyclic ring system of 4 to 12 ring atoms, in particular 5 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Particular examples of “heteroaryl” are for instance pyrazolyl, triazolyl and pyridyl, more particular examples are for instance pyrazol-1-yl, triazol-1-yl, 2-pyridyl and 1H-pyrazol-3-yl. The term “heteroarylalkyl”, alone or in combination, signifies a “heteroaryl” group that is attached to an “alkyl” group and wherein said “alkyl” group is further linked to the compound of formula (I). The term “hydroxyalkyl”, alone or in combination, signifies a “hydroxy” group that is attached to an “alkyl” group and wherein said “alkyl” group is further linked to the compound of formula (I). The term “alkoxyalkyl”, alone or in combination, signifies a “alkoxy” group that is attached to an “alkyl” group and wherein said “alkyl” group is further linked to the compound of formula (I). The term “aryl”, alone or in combination, signifies a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moiet ies include phenyl and naphthyl. Phenyl is a particular example of “aryl”. The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. Particular examples of “alkoxy” are methoxy and ethoxy.The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. A particular example of “alkoxy” is methoxy. The term “oxy”, alone or in combination, signifies the -O- group. The term “oxo”, alone or in combination, signifies the =O group. The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens. The term “fluoro”, alone or in combination, signifies fluorine. The term “fluoro” in combination with another group, denotes the substitution of said group with at least one fluorine, particularly substituted with one to three fluorines, i.e. one, two or three fluorines. The term “haloalkyl”, alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. A particular “haloalkyl” is trifluoromethyl. The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group. The term “carbonyl”, alone or in combination, signifies the -C(O)- group. The term “amino”, alone or in combination, signifies the primary amino group ( -NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-). The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p - toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition these salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particular pharmaceutically acceptable salts of compounds of formula (I) are the salts of trifluoroacetic acid, hydrochloric acid, formic acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid. If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p- methoxybenzyloxycarbonyl (Moz). A particularly preferred protecting group is tert - butoxycarbonyl (Boc). The compound of formula (I) can contain several asymmetric centers and can be present in the form of several stereoisomers, for example optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereo-isomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. Pharmaceutically acceptable enantiomers, racemates and diasteroisomers, refer to those stereoisomers which retain the biological effectiveness and properties of the compound of formula (I), which are not biologically or otherwise undesirable. The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration. If any discrepancy exists between a structure and its name, the structure prevails. The invention thus relates to: A compound according to the invention, wherein the compound is a compound of formula (Ia) A is -O- or -NR1’-; R1 is alkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl; R1’ is hydrogen; or R1 and R1’, together with the -N- atom to which they are attached, form heterocycloalkyl optionally substituted with R4; R2is aryl or cycloalkyl, wherein aryl and cycloalkyl are at each instance optionally substituted with R5; R4 is aryl, heteroaryl, heterocycloalkyl, cyanoaryl or haloaryl; and R5 is alkoxy, halo or haloalkyl; or a pharmaceutically acceptable salt thereof; A compound according to the invention, wherein A is -NR1’-; A compound according to the invention, wherein A is -O-; A compound according to the invention, wherein R1is methyl, ethyl, isopropyl, pyridylmethyl, pyrazolylmethyl, hydroxyethyl, methoxyethyl or cyclopropyl; A compound according to the invention, wherein R1 is methyl, ethyl, isopropyl, 2- pyridylmethyl, 1H-pyrazol-3-ylmethyl, hydroxyethyl, methoxyethyl or cyclopropyl; A compound according to the invention, wherein R1’is hydrogen; A compound according to the invention, wherein R1 and R1’, together with the -N- atom to which they are attached, form heterocycloalkyl optionally substituted with R4; A compound according to the invention, wherein R1and R1’, together with the -N- atom to which they are attached, form heterocycloalkyl selected from azetidin-1-yl, piperazin-1-yl, 1-piperidyl, 3-azaspiro[5.5]undecan-3-yl, 2-azaspiro[4.5]decan-2-yl, 2-azaspiro[4.4]nonan-2-yl and pyrrolidin-1-yl, and wherein said heterocycloalkyl is optionally substituted with R4; A compound according to the invention, wherein R2is phenyl, cyclobutyl, or cyclohexyl, and wherein phenyl, cyclobutyl and cyclohexyl are at each instance optionally substituted with R5; A compound according to the invention, wherein R2is phenyl, cyclobutyl, or cyclohexyl; A compound according to the invention, wherein R2’ is phenyl, cyclobutyl, or cyclohexyl; A compound according to the invention, wherein both R2and R2’are phenyl at each instance optionally substituted with R5; A compound according to the invention, wherein R3is hydrogen; A compound according to the invention, wherein R4 is phenyl, pyridinyl, pyrazolyl, triazolyl, piperidinyl, cyanophenyl or chlorophenyl; A compound according to the invention, wherein R4 is phenyl, 2-pyridyl, pyrazol-1-yl, triazol-1-yl, 1-piperidyl, 4-cyanophenyl, 2-chlorophenyl or 3-chlorophenyl; A compound according to the invention, wherein R5is methoxy, fluoro or trifluoromethyl; and A compound according to the invention, wherein p is 0 or 1, in particular wherein p is 1. The invention further relates to a compound according to the invention selected from Ethyl 2-[prop-2-ynoyl-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate; N-[2-(Methylamino)-2-oxo-ethyl]-N-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]prop-2- ynamide; N-[(2S)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide; N-[(2R)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-pyrazol-1-ylpyrrolidin-1-yl)ethyl]prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(triazol-1-yl)pyrrolidin-1-yl]ethyl]prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3R)-3-(1-piperidyl)pyrrolidin-1-yl]ethyl]prop-2- ynamide; N-[2-(2-Azaspiro[4.4]nonan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-[2-(2-Azaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-[2-(3-Azaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(4-phenyl-1-piperidyl)ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-phenylpiperazin-1-yl)ethyl]prop-2-ynamide; N-[2-[3-(4-Cyanophenyl)azetidin-1-yl]-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-(isopropylamino)-2-oxo-ethyl]prop-2-ynamide; N-[2-(Cyclopropylamino)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-(2-methoxyethylamino)-2-oxo-ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-(2-hydroxyethylamino)-2-oxo-ethyl]prop-2-ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(2- pyridylmethylamino)ethyl]prop-2-ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(1H-pyrazol-3- ylmethylamino)ethyl]prop-2-ynamide; N-[2-(4-Fluorophenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide; N-[2-(Methylamino)-2-oxo-ethyl]-N-[2-phenyl-2-[4-(trifluoromethyl)phenyl]ethyl]prop- 2-ynamide; N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(3-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide; N-[2-[3-(3-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide; N-[2-[3-(2-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide; N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop- 2-ynamide; and N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(2-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide; or a pharmaceutically acceptable salt thereof. The invention also relates to a compound according to the invention selected from Ethyl 2-[prop-2-ynoyl-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate; N-[2-(Methylamino)-2-oxo-ethyl]-N-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]prop-2- ynamide; N-[(2S)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide; N-[(2R)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-pyrazol-1-ylpyrrolidin-1-yl)ethyl]prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(triazol-1-yl)pyrrolidin-1-yl]ethyl]prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3R)-3-(1-piperidyl)pyrrolidin-1-yl]ethyl]prop-2- ynamide; N-[2-(2-Azaspiro[4.4]nonan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-[2-(2-Azaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-[2-(3-Azaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(4-phenyl-1-piperidyl)ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-phenylpiperazin-1-yl)ethyl]prop-2-ynamide; N-[2-[3-(4-Cyanophenyl)azetidin-1-yl]-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-(isopropylamino)-2-oxo-ethyl]prop-2-ynamide; N-[2-(Cyclopropylamino)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-(2-methoxyethylamino)-2-oxo-ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-(2-hydroxyethylamino)-2-oxo-ethyl]prop-2-ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(2- pyridylmethylamino)ethyl]prop-2-ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(1H-pyrazol-3- ylmethylamino)ethyl]prop-2-ynamide; N-[2-(4-Fluorophenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide; N-[2-(Methylamino)-2-oxo-ethyl]-N-[2-phenyl-2-[4-(trifluoromethyl)phenyl]ethyl]prop- 2-ynamide; N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(3-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide; N-[2-[3-(3-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide; N-[2-[3-(2-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide; N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop- 2-ynamide; and N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(2-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide. Processes for the manufacture of a compound of formula (I) as described herein are also an object of the invention. The preparation of a compound of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following scheme 1 and in the description of specific examples. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary. The reaction sequence is not limited to the one displayed in scheme 1, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art. Scheme 1 In the above scheme, A, R1, R2, R2’, R3 and p are as described herein. A propynamide based compound of general formula I can be obtained for example by alkylation of amine 1 with an appropriately substituted bromoacetate or bromoacetamide of formula 2 to yield the desired amine 3. Amide coupling of amine 3 with a propiolic acid 4 with a coupling agent such as DIC or DCC yields the desired propynamide compound of formula I. Generally speaking, the sequence of steps used to synthesize the compound of formula I and further functionalization can also be modified in certain cases. The compound of formula (I) may be prepared in accordance with Scheme 1 or as described in the examples. The starting materials are commercially available or may be prepared in accordance with known methods. Insofar as their preparation is not described in the examples, the compound of formula (I) as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth herein. It will be appreciated that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion to the parent compound in vivo. The invention also relates to a compound according to the invention when manufactured according to a process of the invention. One embodiment of the invention relates to a process for the preparation of a compound according to the invention, comprising the reaction of a compound of formula (B1) with a compound of formula in presence of a suitable solvent and a suitable coupling agent; in the above process, A, R1, R2, R2’, R3and p are as described herein. In the above process, the solvent can be for instance DCM. In the above process, the coupling agent can be for instance DIC or DCC. The invention further relates to: A compound according to the invention for use as therapeutically active substance; A pharmaceutical composition comprising a compound according to the invention and a therapeutically inert carrier; A compound according to the invention for use in the treatment or prophylaxis of cancer, in particular non-small cell lung cancer; The use of a compound according to the invention for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer; The use of a compound according to the invention for the preparation of a medicament for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer; and A method for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, which method comprises administering an effective amount of a compound according to the invention to a patient in need thereof. Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skill ed in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). Example A Film coated tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat. Example B Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg The components are sieved and mixed and filled into capsules of size 2. Example C Injection solutions can have the following composition: Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized. The invention thus also relates in particular to: A compound according to the invention for use as therapeutically active substance; A pharmaceutical composition comprising a compound according to the invention and a therapeutically inert carrier; A compound according to the invention for use in the treatment or prophylaxis of cancer; A compound according to the invention for use in the treatment or prophylaxis of non- small cell lung cancer; The use of a compound according to the invention for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer; The use of a compound according to the invention for the preparation of a medicament for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer; and A method for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, which method comprises administering an effective amount of a compound according to the invention to a patient in need thereof. A certain embodiment of the invention relates to a pharmaceutical composition comprising the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance. A certain embodiment of the invention relates to the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the use in the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, characterized an EGFR exon20 insertion mutation. A certain embodiment of the invention relates to the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the use in the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, characterized by at least one EGFR exon20 insertion mutation selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH and V774_C775insHV. A certain embodiment of the invention relates to the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the use in the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, characterized by an EGFR exon20 insertion mutation selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH and V774_C775insHV. A certain embodiment of the invention relates to a method for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, wherein at least one EGFR mutation selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, N771_P772insH, H773_V774insH, H773_V774insNPH and V774_C775insHV is present in the cancer, which method comprises administering an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Furthermore, the invention includes all substituents in its corresponding deuterated form, wherever applicable, of the compound of formula (I). Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compound of formula (I). The compound of formula (I) may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate. Also an embodiment of the present invention is a compound of formula (I) as described herein, when manufactured according to any one of the described processes. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used as a medicament (e.g. in the form of a pharmaceutical preparation). The pharmaceutical preparation can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topical ocularly (e.g. in the form of solutions, ointments, gels or water soluble polymeric inserts). However, the administration can also be effected parenterally, such as intramuscularly, intravenously, or intraocularly (e.g. in the form of sterile injection solutions). The compound of formula (I) or a pharmaceutically acceptable salt thereof can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées, hard gelatin capsules, injection solutions or topical formulations Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules. Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc. Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art. Moreover, the pharmaceutical preparation can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparation can also contain still other therapeutically valuable substances. Experimental Part The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. Abbreviations: CAS = chemical abstract service; DCC = dicyclohexyl carbodiimide; DCM = dichloromethane; DMSO = dimethyl sulfoxide; DIC = N,N-diisopropylcarbodiimide; DIEA = N,N- Diisopropylethylamine; HPLC = high-performance liquid chromatography; MS = mass spectrometry; SFC = supercritical fluid chromatography; TFA = trifluoroacetic acid; THF = tetrahydrofuran. Example 1 Ethyl 2-[prop-2-ynoyl-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate Step 1: Ethyl 2-[[(2RS)-2- acetate (2-Cyclohexyl-2-phenyl-ethyl)amine hydrochloride (CAS 92320-99-5) (2.0 g, 8.34 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (40 mL). DIEA (3.23 g, 4.3 mL, 25.0 mmol, 3.0 equiv.) and ethyl bromoacetate (1.46 g, 8.76 mmol, 1.05 equiv.) were added and the mixture was stirred at 25 °C for 16 hours. The reaction was quenched with water, and then the product was extracted with ethyl acetate two times and then washed with water and brine. The combined organic layers were dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (80 g, 20-100% ethyl acetate in heptane) affording the title compound (1.4 g, 55%) as a light yellow liquid. MS: m / e = 290.3 (M+H+). Step 2: Ethyl 2-[prop-2-ynoyl-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate Ethyl 2-[[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate (Example 1, step 1) (145 mg, 0.50 mmol, 1.0 equiv.) was dissolved in dichloromethane (1 mL). Propiolic acid (38.6 mg, 0.034 mL, 0.55 mmol, 1.1 equiv.) and N,N-diisopropylcarbodiimide (69.5 mg, 0.086 mL, 0.55 mmol, 1.1 equiv.) were added and the mixture was stirred at 25 °C for 30 minutes. The reaction was concentrated to dryness and the crude product was purified by flash column chromatography on silica gel (12 g, 0-50% ethyl acetate in heptane) affording the title compound (93 mg, 50%) as a colorless oil. MS: m / e = 342.3 (M+H+). Example 2 N-[2-(Methylamino)-2-oxo-ethyl]-N-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]prop-2-ynamide 1 M NaOH in water (54 µL, 53.89 was added to a clear solution of ethyl 2- [prop-2-ynoyl-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate (Example 1, step 2) (20 mg, 53.89 µmol, 1.0 equiv.) in tetrahydrofuran, extra dry (200 uL) and methanol (200 uL) and the reaction was stirred at 25 °C for 30 minutes. 1 M HCl (65.7 mg, 54 µL, 53.89 µmol, 1.0 equiv.) was added and the mixture was concentrated with toluene three times. The material was dissolved in dichloromethane, extra dry (200 µL). Methanamine hydrochloride (CAS 593-51-1) (3.6 mg, 53.89 µmol, 1.0 equiv.), N,N-diisopropylcarbodiimide (7.5 mg, 9.24 µL, 59.28 µmol, 1.1 equiv.) and DIEA (7.0 mg, 9 µL, 53.89 µmol, 1.0 equiv.) were added and the reaction was stirred at 25 °C for 30 minutes. The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (4 g, 0-100% ethyl acetate in heptane) affording the title compound (2.3 mg, 12%) as a colorless oil. MS: m / e = 327.4 (M+H+). Example 3 N-[(2S)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide or N-[(2R)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3- phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide Step 1: N-[ - - oxo- - 1- yl]ethyl]prop-2-ynamide The title compound was as a mg, , MS: m / e = 443.4 (M+H+) using chemistry similar to that described in Example 2 starting from ethyl 2-[prop-2-ynoyl- [(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate (Example 1, step 2) and (3S)-3- phenylpyrrolidine hydrochloride (CAS 1094670-20-8). Step 2: N-[(2S)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide or N-[(2R)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3- phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide N-[(2RS)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1-yl]ethyl]prop- 2-ynamide (Example 3, step 1) (15 mg) was submitted to SFC for separation of the epimers (Column chiral Whelk, 5 µm, 250 x 20 mm, 40% EtOH, first eluting peak) affording the title compound (4.1 mg, 27%) as a white solid. MS: m / e = 443.4 (M+H+). Example 4 N-[(2R)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide or N-[(2S)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3- phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide N-[(2RS)-2- - oxo- - yl]ethyl]prop- 2-ynamide (Example 3, step 1) (15 mg) was submitted to SFC for separation of the epimers (Column chiral Whelk, 5 µm, 250 x 20 mm, 40% EtOH, second eluting peak) affording the title compound (4.8 mg, 32%) as a white solid. MS: m / e = 443.4 (M+H+). Example 5 N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide Step 1: Methyl 2-[2,2- acetate The title compound was obtained as a light yellow oil (3.3 g, 67%), MS: m / e = 321.2 (M+H+) using chemistry similar to that described in Example 1, step 2 starting from methyl 2-(2,2- diphenylethylamino)acetate (CAS 1632314-99-8). Step 2: 2-[2,2-Diphenylethyl(prop-2-ynoyl)amino]acetic acid Methyl 2-[2,2-diphenylethyl(prop- acetate (Example 5, step 1) (1 g, 3.11 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (20 mL) and water (3.33 mL). hydroxylithium;hydrate (392 mg, 9.34 mmol, 3.0 equiv.) was added and the reaction was stirred for 2 hours at 0 °C. 1 M aq. HCl (14.9 g, 12.45 mL, 12.45 mmol, 4.0 equiv.) was added and the reaction was concentrated in vacuo to obtain the title compound (790 mg, 79%) as a white solid. MS: m / e = 308.2 (M+H+). Step 3: N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide 2-[2,2-Diphenylethyl(prop-2- mg, 208.24 µmol, 1.0 equiv.) was dissolved in acetonitrile, extra dry (1 mL) and the reaction was stirred for 5 minutes. 2,4,6- Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) 50 % solution in ethyl acetate (265 mg, 245 µL, 416.48 µmol, 2.0 equiv.) and DIEA (161 mg, 218 µL, 1.25 mmol, 6.0 equiv.) was added. (3S)-3-phenylpyrrolidine;hydrochloride (CAS 1094670-20-8) (45 mg, 270.71 µmol, 1.3 equiv.) was dissolved in acetonitrile, extra dry (500 µL), DIEA (54 mg, 72.74 µL, 416.48 µmol, 2.0 equiv.) and N,N-dimethylformamide, extra dry (200 µL) and was added to the reaction which was stirred for 1 hour. The solvent was evaporated and the crude was purified by reverse phase column chromatography (15g, C18, silica gel, 0-100 % acetonitrile in water) to obtain the title compound (14 mg, 15 %) as orange powder. MS: m / e = 437.222 (M+H+). Example 6 N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop-2-ynamide The title compound was obtained as a mg, , MS: m / e = 438.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 2-pyrrolidin-3-ylpyridine (CAS 150281-45- 1). Example 7 N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-pyrazol-1-ylpyrrolidin-1-yl)ethyl]prop-2-ynamide The title compound was as a (40 mg, 41%), MS: m / e = 427.213 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2- diphenylethyl(prop-2-ynoyl)amino]acetic acid (Example 5, step 2) and 1-pyrrolidin-3- ylpyrazole;dihydrochloride (CAS 1242339-08-7). Example 8 N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(triazol-1-yl)pyrrolidin-1-yl]ethyl]prop-2-ynamide The title compound was as a mg, , MS: m / e = 428.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 1-pyrrolidin-3-yltriazole;dihydrochloride (CAS 1955557-41-1). Example 9 N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3R)-3-(1-piperidyl)pyrrolidin-1-yl]ethyl]prop-2- ynamide The title compound was as a mg, , MS: m / e = 444.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 1-[(3R)-pyrrolidin-3- yl]piperidine;dihydrochloride (CAS 913702-35-9). Example 10 N-[2-(2-Azaspiro[4.4]nonan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide The title compound was obtained as a mg, 27%), MS: m / e = 415.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 12-azaspiro[4.4]nonane (CAS 175-94-0). Example 11 N-[2-(2-Azaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide The title compound was obtained as a mg, , MS: m / e = 429.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 2-azaspiro[4.5]decane;hydrochloride (CAS 36392-74-2). Example 12 N-[2-(3-Azaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide The title compound was obtained as a white solid (29 mg, 41%), MS: m / e = 443.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 3-azaspiro[5.5]undecane (CAS 180-44-9). Example 13 N-(2,2-Diphenylethyl)-N-[2-oxo-2-(4-phenyl-1-piperidyl)ethyl]prop-2-ynamide The title compound was as a mg, , MS: m / e = 451.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 4-phenylpiperidine (CAS 771-99-3). Example 14 N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-phenylpiperazin-1-yl)ethyl]prop-2-ynamide Step 1: tert-Butyl 4-[2-[2,2-diphenylethyl(prop-2-ynoyl)amino]acetyl]-2-phenyl-piperazine-1- carboxylate The title compound was obtained as a white solid (40 mg, 45%), MS: m / e = 552.5 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and tert-butyl 2-phenylpiperazine-1-carboxylate (CAS 886766-60-5). Step 2: N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-phenylpiperazin-1-yl)ethyl]prop-2-ynamide Tert-butyl 4-[2-[2,2-diphenylethyl(prop-2-ynoyl)amino]acetyl]-2-phenyl-piperazine-1- carboxylate (Example 14, step 1) (30.0 mg, 0.05 mmol, 1.0 equiv.) was dissolved in DCM (2 mL) and TFA (0.4 mL) and was stirred at 25 °C for 2 hours. The solvent was evaporated and the residue was purified by preparative HPLC (15 to 45% acetonitrile in water) to obtain the title compound (30.0 mg, 92%) as a white solid. MS: m / e = 452.1 (M+H+) Example 15 N-[2-[3-(4-Cyanophenyl)azetidin-1-yl]-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide The title compound was obtained as a white solid (32 mg, 21%), MS: m / e = 448.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 4-(azetidin-3-yl)benzonitrile (CAS 7215-03- 4). Example 16 N-(2,2-Diphenylethyl)-N-[2-(isopropylamino)-2-oxo-ethyl]prop-2-ynamide The title compound was obtained as a mg, 34%), MS: m / e = 349.1 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and propan-2-amine (CAS 75-31-0). Example 17 N-[2-(Cyclopropylamino)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide The title compound was obtained as a mg, 43%), MS: m / e = 347.1 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and cyclopropanamine (CAS 765-30-0). Example 18 N-(2,2-Diphenylethyl)-N-[2-(2-methoxyethylamino)-2-oxo-ethyl]prop-2-ynamide The title compound was obtained as a white solid (35 mg, 29%), MS: m / e = 365.2 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 2-methoxyethanamine (CAS 109-85-3). Example 19 N-(2,2-Diphenylethyl)-N-[2-(2-hydroxyethylamino)-2-oxo-ethyl]prop-2-ynamide The title compound was obtained as a mg, 51%), MS: m / e = 351.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[2,2-diphenylethyl(prop- 2-ynoyl)amino]acetic acid (Example 5, step 2) and 2-aminoethanol (CAS 141-43-5). Example 20 N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2-ynamide Step 1: 2-[[2-(4-Methoxyphenyl)- - methyl-acetamide 2-(4-Methoxyphenyl)-2-phenyl-ethanamine;hydrochloride (CAS 21998-49-2) (250 mg, 0.948 mmol, 1.0 equiv.) was dissolved in N,N-dimethylformamide (2.5 mL). Potassium carbonate (393 mg, 2.84 mmol, 3.0 equiv.) and 2-bromo-N-methyl-acetamide (144 mg, 0.948 mmol, 1.0 equiv.) were added and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (40gr, 20-100% ethyl acetate in heptane and 0-10% methanol in dichloromethane) to obtain the title compound as a colorless oil. MS: m / e = 299.2 (M+H+) Step 2: N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide The title compound was obtained as a mg, 42%), MS: m / e = 351.2 (M+H+) using chemistry similar to that described in Example 1, step 2 starting from 2-[[2-(4- methoxyphenyl)-2-phenyl-ethyl]amino]-N-methyl-acetamide (Example 20, step 1). Example 21 N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(2-pyridylmethylamino)ethyl]prop-2- ynamide Step 1: Methyl 2-[[2-(4-methoxyphenyl)-2-phenyl-ethyl]amino]acetate The title compound was obtained as a colorless oil (360 mg, 62%), MS: m / e = 300.2 (M+H+) using chemistry similar to that described in Example 1, step 1 starting from 2-(4-methoxyphenyl)- 2-phenyl-ethanamine;hydrochloride (CAS 21998-49-2) and methyl 2-bromoacetate. Step 2: Methyl 2-[[2-(4-methoxyphenyl)-2-phenyl-ethyl]-prop-2-ynoyl-amino]acetate The title compound was obtained as a mg, 58%), MS: m / e = 352.2 (M+H+) using chemistry similar to that described in Example 1, step 2 starting from methyl 2-[[2-(4- methoxyphenyl)-2-phenyl-ethyl]amino]acetate (Example 21, step 1). Step 3: 2-[[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-prop-2-ynoyl-amino]acetic acid The title compound was obtained as a light yellow oil (350 mg, 58%), MS: m / e = 338.2 (M+H+) using chemistry similar to that described in Example 5, step 2 starting from methyl 2-[[2-(4- methoxyphenyl)-2-phenyl-ethyl]-prop-2-ynoyl-amino]acetate (Example 21, step 2). Step 4: N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(2- pyridylmethylamino)ethyl]prop-2-ynamide The title compound was as a mg, , MS: m / e = 428.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[[2-(4-methoxyphenyl)- 2-phenyl-ethyl]-prop-2-ynoyl-amino]acetic acid (Example 21, step 3) and 2-pyridylmethanamine (CAS 3731-51-9). Example 22 N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(1H-pyrazol-3- ylmethylamino)ethyl]prop-2-ynamide The title compound was as a mg, , MS: m / e = 417.3 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[[2-(4-methoxyphenyl)- 2-phenyl-ethyl]-prop-2-ynoyl-amino]acetic acid (Example 21, step 3) and 1H-pyrazol-3- ylmethanamine (CAS 37599-58-9). Example 23 N-[2-(4-Fluorophenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2-ynamide Step 1: 2-[[2-(4-Fluorophenyl)-2-phenyl-ethyl]amino]-N-methyl-acetamide The title compound was obtained as a colorless oil (154 mg, 49%), MS: m / e = 287.2 (M+H+) using chemistry similar to that described in Example 20, step 1 starting from 2-(4-fluorophenyl)- 2-phenyl-ethanamine;hydrochloride (79314-49-1). Step 2: N-[2-(4-Fluorophenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide The title compound was obtained as a mg, 42%), MS: m / e = 339.1 (M+H+) using chemistry similar to that described in Example 1, step 2 starting from 2-[[2-(4- fluorophenyl)-2-phenyl-ethyl]amino]-N-methyl-acetamide (Example 23, step 1). Example 24 N-[2-(Methylamino)-2-oxo-ethyl]-N-[2-phenyl-2-[4-(trifluoromethyl)phenyl]ethyl]prop-2- ynamide Step 1: N-Methyl-2-[[2-phenyl-2-[4-(trifluoromethyl)phenyl]ethyl]amino]acetamide The title compound was obtained as a light yellow oil (142 mg, 46%), MS: m / e = 337.5 (M+H+) using chemistry similar to that described in Example 20, step 1 starting from 2-phenyl-2-[4- (trifluoromethyl)phenyl]ethanamine;hydrochloride (CAS 21979-89-5). Step 2: N-[2-(Methylamino)-2-oxo-ethyl]-N-[2-phenyl-2-[4- (trifluoromethyl)phenyl]ethyl]prop-2-ynamide The title compound was obtained as a mg, 29%), MS: m / e = 389.2 (M+H+) using chemistry similar to that described in Example 1, step 2 starting from N-methyl-2-[[2-phenyl-2- [4-(trifluoromethyl)phenyl]ethyl]amino]acetamide (Example 24, step 1). Example 25 N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(3-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide Step 1: Methyl 2-[(2-cyclobutyl-2-phenyl-ethyl)amino]acetate The title compound was obtained as a light yellow oil (1.2 g, 46%), MS: m / e = 248.1 (M+H+) using chemistry similar to that described in Example 1, step 1 starting from 2-cyclobutyl-2- phenyl-ethanamine;hydrochloride (CAS 2580243-11-2) and methyl 2-bromoacetate. Step 2: Methyl 2-[(2-cyclobutyl-2-phenyl-ethyl)-prop-2-ynoyl-amino]acetate The title compound was obtained as a mg, 55%), MS: m / e = 300.2 (M+H+) using chemistry similar to that described in Example 1, step 2 starting from methyl 2-[(2- cyclobutyl-2-phenyl-ethyl)amino]acetate (Example 25, step 1). Step 3: 2-[(2-Cyclobutyl-2-phenyl-ethyl)-prop-2-ynoyl-amino]acetic acid The title compound was obtained as a yellow oil (274 mg, quantitative yield), MS: m / e = 286.2 (M+H+) using chemistry similar to that described in Example 5, step 2 starting from methyl 2- [(2-cyclobutyl-2-phenyl-ethyl)-prop-2-ynoyl-amino]acetate (Example 25, step 2). Step 4: N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(3-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide The title compound was obtained as a mg, 18%), MS: m / e = 415.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[(2-cyclobutyl-2- phenyl-ethyl)-prop-2-ynoyl-amino]acetic acid (Example 25, step 3) and 3- phenylpyrrolidine;hydrochloride (CAS 857281-02-8). Example 26 N-[2-[3-(3-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide The title compound was as a mg, , MS: m / e = 449.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[(2-cyclobutyl-2-phenyl- ethyl)-prop-2-ynoyl-amino]acetic acid (Example 25, step 3) and 3-(3-chlorophenyl)pyrrolidine (CAS 914299-59-5). Example 27 N-[2-[3-(2-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide The title compound was as a mg, , MS: m / e = 449.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[(2-cyclobutyl-2-phenyl- ethyl)-prop-2-ynoyl-amino]acetic acid (Example 25, step 3) and 3-(2- chlorophenyl)pyrrolidine;hydrochloride (CAS 1095545-14-4). Example 28 N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop-2- ynamide The title compound was as a mg, , MS: m / e = 416.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[(2-cyclobutyl-2-phenyl- ethyl)-prop-2-ynoyl-amino]acetic acid (Example 25, step 3) and 2-pyrrolidin-3-ylpyridine (CAS 150281-45-1). Example 29 N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(2-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide The title compound was obtained as a white solid (16 mg, 36%), MS: m / e = 415.4 (M+H+) using chemistry similar to that described in Example 5, step 3 starting from 2-[(2-cyclobutyl-2-phenyl- ethyl)-prop-2-ynoyl-amino]acetic acid (Example 25, step 3) and 2-phenylpyrrolidine (CAS 1006- 64-0). Example 30 CUTO HTRF Phospho EGFR SVD assay (cellular) Cell line and media CUTO-18 cell line, bearing the D770_N771insSVD mutation, was obtained from University of Colorado (Aurora, CO, USA). Cells were maintained at 37 °C, 5% CO2in RPMI 1640 (Gibco 61870036) supplemented with 10% fetal bovine serum (FBS) (Gibco). Freeze medium was culture medium + 10% FBS (extra) + 10% DMSO. Protocol Cells were thawed, transferred to a 50 ml tube and assay medium (RPMI 1640 Medium, no phenol red (Gibco 11835030)) was added up to a volume of 10 ml. Cell suspension was spun for 5 min at 1000 rpm. Supernatant was removed, pellet was diluted in assay medium and cell concentration was adjusted to 3.2 mio cells / ml.62.5 nl compound (in dose response) or DMSO were transferred to Greiner Bio-One, Nr.784-075 microtiter plate using an Echo liquid dispenser (Beckman Coulter). Cells were dispensed to Greiner Bio-One, Nr.784-075 micro- titer plate at 40000 cells / well in 12.5 μl assay medium (except rows A and P). Outer wells received 17.5 μl PBS as evaporation barrier. Column 2 (blank control) received 12.5 μl assay medium without cells (except rows A and P). Cells were incubated with compounds for 4 hours at 37 °C, 5% CO2, 95% humidity. Following the incubation, 4 µl / well of the supplemented lysis buffer (Cis-bio, Phospho-EGFR HTRF kit, 64EG1PEH plus 2mM (f.c.) Sodium ortho- vanadate (Alfa Aeser J60191)) were added to all wells except outer rows, followed by a 30 minute incubation at room temperature with shaking (400 rpm). The covered plates were then frozen and stored overnight at -80 °C. On the next day and after thawing the plates, 4 µl of a mixture of anti-Phospho-EGFR Cryptate and of anti-Phospho-EGFR-d2 antibody solutions prepared in the supplied detection buffer was added to each well except outer rows. The lidded plates were then incubated for 4 hours at room temperature before reading the fluorescence emission at 616 and 665 nm using a PHERAstar FSX plate reader (BMG). Data was analyzed in using the normalized ratio of the 665 to 616 signals multiplied by 10000. Blank values were subtracted from all samples, before normalizing the signals to the DMSO control to determine the final pEGFR signal: ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ − ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^) ∗ 100 % ^^ ^^ ^^ ^^ ^^ = ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ − ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ Example 31 NCI-H2073 HTRF Phospho EGFR WT assay (cellular) Cell line and media NCI-H2073 cell line was obtained from ATCC - American Type Culture Collection. Cells were maintained at 37 °C, 5% CO2 in RPMI-1640 (ATCC) (Gibco A10491) supplemented with 5% fetal bovine serum (FBS) (Gibco) and 1ng / ml recombinant human Epidermal Growth Factor (rhEGF) (R&D Systems 236-EG). Freeze medium was culture medium + 10% FBS (extra) + 10% DMSO. Protocol Cells were thawed, transferred to a 50 ml tube and assay medium (RPMI 1640 Medium, no phenol red (Gibco 11835030)) was added up to a volume of 10 ml (per vial of frozen cells containing 1E+7 cells in 1 ml for one assay plate). Cell suspension was spun for 5 min at 1000 rpm. Supernatant was removed, pellet was diluted in assay medium and cell concentration was adjusted to 1.6 mio cells / ml.62.5 nl compound (in dose response) or DMSO were transferred to Greiner Bio- One, Nr.784-075 microtiter plate using an Echo liquid dispenser (Beckman Coulter). Cells were dispensed to Greiner Bio-One, Nr.784-075 micro-titer plate at 20000 cells / well in 12.5 μl assay medium (except rows A and P). Outer wells received 17.5 μl PBS as evaporation barrier. Column 2 (blank control) received 12.5 μl assay medium without cells (except rows A and P). Plate was spun for 30 sec at 300 rpm. Cells were incubated with compounds for 4 hours at 37 °C, 5% CO2, 95% humidity. Following the incubation, 4 µl / well of the supplemented lysis buffer (Cis-bio, Phospho- EGFR HTRF kit, 64EG1PEH plus 2mM (f.c.) Sodium ortho-vanadate (Alfa Aeser J60191)) were added to all wells except outer rows, followed by a 30 min incubation at room temperature with shaking (400 rpm). Following the cell lysis, 4 µl of a mixture of anti-Phospho-EGFR Cryptate and of anti-Phospho-EGFR-d2 antibody solutions prepared in the supplied detection buffer was added to each well except outer rows. Plates were spun for 10 sec at 1000 rpm. The lidded plates were then incubated for 4 hours at room temperature in the dark before reading the fluorescence emission at 616 and 665 nm using a PHERAstar FSX plate reader (BMG). Data was analyzed in using the normalized ratio of the 665 to 616 signals multiplied by 10000. Blank values were subtracted from all samples, before normalizing the signals to the DMSO control to determine the final pEGFR signal: ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ − ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^) ∗ 100 % ^^ ^^ ^^ ^^ ^^ = ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ − ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ The in Table 1. Table 1: CUTO cellular HTRF Phospho EGFR SVD and NCI-H2073 cellular HTRF Phospho EGFR WT assay data CUTO NCI- Example Structure SVD H2073 WT IC50 (µM) IC50 (µM)

Claims

Claims 1. A compound of formula (I) whereinA is -O- or -NR1’-; R1 is alkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl; R1’is hydrogen or alkyl; or R1and R1’, together with the -N- atom to which they are attached, form heterocycloalkyl optionally substituted with R4; R2 and R2’ are both independently selected from aryl and cycloalkyl, wherein aryl and cycloalkyl are at each instance optionally substituted with R5; R3is hydrogen or alkyl; R4 is aryl, heteroaryl, heterocycloalkyl, cyanoaryl or haloaryl; R5 is alkoxy, halo or haloalkyl; and, p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ia)a) wherein A is -O- or -NR1’-; R1is alkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl; R1’ is hydrogen; or R1 and R1’, together with the -N- atom to which they are attached, form heterocycloalkyl optionally substituted with R4; R2is aryl or cycloalkyl, wherein aryl and cycloalkyl are at each instance optionally substituted with R5; R4 is aryl, heteroaryl, heterocycloalkyl, cyanoaryl or haloaryl; and R5 is alkoxy, halo or haloalkyl; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein A is -NR1’-.

4. The compound according to any one of claims 1 to 3, wherein R1 is methyl, ethyl, isopropyl, pyridylmethyl, pyrazolylmethyl, hydroxyethyl, methoxyethyl or cyclopropyl.

5. The compound according to any one of claims 1 to 4, wherein R1’ is hydrogen.

6. The compound according to any one of claims 1 to 5, wherein R1 and R1’ together with the -N- atom to which they are attached, form heterocycloalkyl optionally substituted with R4.

7. The compound according to any one of claims 1 to 6, wherein R2 is phenyl, cyclobutyl, or cyclohexyl, and wherein phenyl, cyclobutyl and cyclohexyl are at each instance optionally substituted with R5.

8. The compound according to any one of claims 1 to 7, wherein R2’ is phenyl, cyclobutyl, or cyclohexyl.

9. The compound according to any one of claims 1 to 8, wherein R3is hydrogen.

10. The compound according to any one of claims 1 to 9, wherein R4 is phenyl, pyridinyl, pyrazolyl, triazolyl, piperidinyl, cyanophenyl or chlorophenyl.

11. The compound according to any one of claims 1 to 10, wherein R5is methoxy, fluoro or trifluoromethyl.

12. The compound according to any one of claims 1 to 11, wherein p is 1.

13. A compound according to the invention selected from Ethyl 2-[prop-2-ynoyl-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]amino]acetate; N-[2-(Methylamino)-2-oxo-ethyl]-N-[(2RS)-2-cyclohexyl-2-phenyl-ethyl]prop-2- ynamide; N-[(2S)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide; N-[(2R)-2-Cyclohexyl-2-phenyl-ethyl]-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1- yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3S)-3-phenylpyrrolidin-1-yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-pyrazol-1-ylpyrrolidin-1-yl)ethyl]prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-[3-(triazol-1-yl)pyrrolidin-1-yl]ethyl]prop-2- ynamide;N-(2,2-Diphenylethyl)-N-[2-oxo-2-[(3R)-3-(1-piperidyl)pyrrolidin-1-yl]ethyl]prop-2- ynamide; N-[2-(2-Azaspiro[4.4]nonan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-[2-(2-Azaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-[2-(3-Azaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(4-phenyl-1-piperidyl)ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-oxo-2-(3-phenylpiperazin-1-yl)ethyl]prop-2-ynamide; N-[2-[3-(4-Cyanophenyl)azetidin-1-yl]-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2- ynamide; N-(2,2-Diphenylethyl)-N-[2-(isopropylamino)-2-oxo-ethyl]prop-2-ynamide; N-[2-(Cyclopropylamino)-2-oxo-ethyl]-N-(2,2-diphenylethyl)prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-(2-methoxyethylamino)-2-oxo-ethyl]prop-2-ynamide; N-(2,2-Diphenylethyl)-N-[2-(2-hydroxyethylamino)-2-oxo-ethyl]prop-2-ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(2- pyridylmethylamino)ethyl]prop-2-ynamide; N-[2-(4-Methoxyphenyl)-2-phenyl-ethyl]-N-[2-oxo-2-(1H-pyrazol-3- ylmethylamino)ethyl]prop-2-ynamide; N-[2-(4-Fluorophenyl)-2-phenyl-ethyl]-N-[2-(methylamino)-2-oxo-ethyl]prop-2- ynamide; N-[2-(Methylamino)-2-oxo-ethyl]-N-[2-phenyl-2-[4-(trifluoromethyl)phenyl]ethyl]prop- 2-ynamide;N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(3-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide; N-[2-[3-(3-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide; N-[2-[3-(2-Chlorophenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-N-(2-cyclobutyl-2-phenyl- ethyl)prop-2-ynamide; N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-[3-(2-pyridyl)pyrrolidin-1-yl]ethyl]prop- 2-ynamide; and N-(2-Cyclobutyl-2-phenyl-ethyl)-N-[2-oxo-2-(2-phenylpyrrolidin-1-yl)ethyl]prop-2- ynamide; or a pharmaceutically acceptable salt thereof.

14. A process for the preparation of a compound according any one of claims 1 to 13, comprising the reaction of a compound of formula (B1) with a compound of formulain presence of a suitable solventagent; in the above process, A, R1, R2, R2’, R3and p are as defined in any one of claims 1 to 13.

15. A compound according any one of claims 1 to 13, when manufactured according to a process of claim 14.

16. A compound according any one of claims 1 to 13, for use as therapeutically active substance.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a therapeutically inert carrier.

18. A compound according to any one of claims 1 to 13 for use in the treatment or prophylaxis of cancer, in particular non-small cell lung cancer.

19. The use of a compound according to any one of claims 1 to 13 for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer.

20. The use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer.

21. A method for the treatment or prophylaxis of cancer, in particular non-small cell lung cancer, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 13 to a patient in need thereof.

22. The invention as hereinbefore described.

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