EGFR inhibitors

Abstract

The present application relates to a compound of general formula (I) The present invention provides a compound having the formula (I), or a pharmaceutically acceptable salt thereof, compositions comprising the compound, and methods of using the compound. The compound of formula (I) can be used as a medicine.

Description

[Technical Field]

[0001] The present invention provides compounds that are selective allosteric inhibitors of EGFR mutations including T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S, their preparation, pharmaceutical compositions containing them, and their use as therapeutically active substances.

[0002] The present invention relates to a compound of formula (I) The present invention provides a novel compound of formula TIFF0007737991000001.tif95170, or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] HER family receptor tyrosine kinases are mediators of cell proliferation, differentiation, and survival. This receptor family includes four distinct members: epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homodimers and heterodimers, and the subsequent activation of intrinsic tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signaling molecules (Yarden, Y., Sliwkowski, MX. Untangling the ErbB signaling network. Nature Review Mol Cell Biol. 2001 Feb;2(2):127-37). Deregulation of EGFR by overexpression or mutation has been implicated in many human cancer types, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly 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 EGFR tyrosine kinase, has been approved in numerous countries for the treatment of recurrent NSCLC.

[0004] Although significant single-agent activity of EGFR tyrosine kinase inhibitors is observed in some NSCLC patients whose tumors harbor somatic kinase domain mutations, clinical benefit is significantly reduced in patients with wild-type EGFR (Paez 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 EGFR mutations are exon 19 deletions, with delta 746-750 being the most common mutation, and exon 21 amino acid substitutions, with L858R being 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).

[0005] Treatment resistance occurs frequently and is often due to a secondary T790M mutation within the ATP site of the receptor. Although several mutation-selective irreversible inhibitors have been developed that are highly active against T790M mutants, their efficacy can be compromised by an acquired C797S mutation, a cysteine ​​residue that forms a key covalent bond (Thress, KSet 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)). Wang further reported that the C797S mutation is a major mechanism of resistance to T790M-targeted 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 causing resistance to osimertinib, such as L718Q, have been described by Yang (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 EGFR L858R / T790M and EGFR L858R / T790M / C797S Resistance mutations in NSCLC: Current developments in medicinal chemistry, Med Res Rev 2018;1-32) is a study on targeting EGFR in the treatment of NSCLC. L858R / T790M and EGFR L858R / T790M / C797Sreported in a review paper on targeting resistance mutations.

[0006] Because most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents that work differently are needed, for example, by targeting drug-resistant EGFR mutations.

[0007] Recent studies suggest that intentional targeting of allosteric sites may 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).

[0008] There is a real need for the generation of selective molecules that specifically inhibit T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S containing EGFR mutations, particularly T790M and C797S containing EGFR mutations, that are useful in the therapeutic and / or prophylactic treatment of cancer. Summary of the Invention

[0009] The compounds of formula (I) described herein have improved EGFR potency and selectivity for EGFR mutants containing T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S, particularly for EGFR mutants containing T790M and C797S, as well as improved physicochemical properties. DETAILED DESCRIPTION OF THE INVENTION

[0010] The term "pharmaceutically acceptable salt" refers to a salt of a compound of Formula (I) that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid (especially 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, and N-acetylcysteine. These salts may also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and 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, polyimine resins, etc. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride, methanesulfonate, and citrate salts.

[0011] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0012] The abbreviation uL stands for microliter and is equivalent to the symbol μL.

[0013] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0014] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0015] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0016] Also, one embodiment of the present invention is a compound of formula (I) as described herein, and pharmaceutically acceptable salts thereof, particularly a compound of formula (I) as described herein.

[0017] Also, an embodiment of the present invention is a compound according to Formula (I) described herein.

[0018] Also, an embodiment of the invention is a compound according to Formula (I) described herein, wherein the compound is 2-[4-chloro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide.

[0019] The present invention therefore also relates to a process for the preparation of a compound according to the invention, which comprises reacting a compound of formula (B1) in the presence of a base and a catalyst TIFF0007737991000002.tif52170 and the compound of formula (B2) TIFF0007737991000003.tif31170, and relates to a process comprising coupling the compounds.

[0020] The coupling can be conveniently carried out in a solvent, which can be, for example, DMF.

[0021] In the coupling, the base may be, for example, trimethylamine, triethylamine, dimethylamine, diethylamine, or diisopropylethylamine. Conveniently, the base is triethylamine.

[0022] In the coupling, the catalyst is Pd(II) with a suitable ligand and Cu(I). A convenient ligand is TPP.

[0023] Convenient conditions for coupling can be between about 20°C and about 120°C, particularly between about 40°C and about 100°C, and more particularly between about 60°C and about 90°C.

[0024] Preferred conditions for coupling are triethylamine in DMF at about 80° C. for about 1 hour to about 24 hours, particularly about 2 hours to about 5 hours.

[0025] The present invention also provides processes for preparing the compounds of formula (I) described herein.

[0026] The preparation of compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art.

[0027] More specifically, the compound of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction order is not limited to that shown in Scheme 1, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods similar to those shown below, methods described in the references or examples cited herein, or methods known in the art.

[0028] Scheme 1 TIFF0007737991000004.tif96170

[0029] Compounds of formula (I) can be obtained, for example, by cyclization of a pre-prepared amino ester 1 with an appropriately substituted methyl 2-(bromomethyl)benzoate of formula 2 to generate the desired isoindoline ester 3. Saponification and amide coupling of an appropriately substituted amine of formula 4 with a coupling agent such as HATU produces the desired amide compound of formula 5. Sonogashira coupling of 5 with an appropriately substituted acetylene of formula 6 produces the desired isoindoline compound of formula (I) (Scheme 1).

[0030] Generally speaking, the order of steps used to synthesize compounds of formula (I), as well as further functionalization, may also be modified in certain cases.

[0031] Unless their preparation is described in the examples, compounds of formula (I) and all intermediate products can be prepared by analogous methods or according to the methods described herein. Starting materials are commercially available, known in the art, or can be prepared by or in analogy with methods known in the art.

[0032] 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 back to the parent compound in vivo.

[0033] Certain embodiments of the present invention relate to compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances.

[0034] Certain embodiments of the present invention relate to compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof for use in the therapeutic and / or prophylactic treatment of cancer, in particular non-small cell lung cancer.

[0035] Certain embodiments of the present invention relate to compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof for use in the therapeutic and / or prophylactic treatment of non-small cell lung cancer.

[0036] Certain embodiments of the present invention relate to the use of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of cancer, in particular non-small cell lung cancer.

[0037] Certain embodiments of the present invention relate to pharmaceutical compositions comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0038] Certain embodiments of the present invention relate to methods for the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer, by administering to a patient a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0039] The present invention also relates, inter alia, to: A compound of formula (I) for use as a therapeutically active substance; a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier; A compound of formula (I) for use in the treatment or prevention of cancer; A compound of formula (I) for use in the treatment or prevention of non-small cell lung cancer; Use of a compound of formula (I) for the treatment or prevention of cancer; Use of a compound of formula (I) for the treatment or prevention of cancer, for the treatment or prevention of non-small cell lung cancer; Use of a compound of formula (I) for the preparation of a medicament for the treatment or prevention of cancer; Use of a compound of formula (I) for the preparation of a medicament for the treatment or prevention of non-small cell lung cancer; A method for the treatment or prevention of cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula (I); and A method for the treatment or prevention of non-small cell lung cancer, comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0040] Certain embodiments of the present invention relate to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients with EGFR activating mutations who are afflicted with cancer, in particular non-small cell lung cancer, comprising determining the EGFR activating mutation status in said patient, followed by administering to said patient a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0041] One particular embodiment of the present invention relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients with EGFR mutations T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S, suffering from cancer, in particular non-small cell lung cancer, comprising determining the EGFR activating mutation status in said patient, followed by administering to said patient a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0042] Certain embodiments of the present invention relate to a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in the therapeutic and / or prophylactic treatment of patients suffering from cancer, in particular non-small cell lung cancer, and having an EGFR activating mutation as determined by the cobas® EGFR Mutation Test v2, comprising determining the EGFR activating mutation status in said patient, followed by administering to said patient a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0043] Furthermore, the present invention includes all substituents of the compounds of formula (I) in their corresponding deuterated forms, where applicable.

[0044] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0045] The compounds of formula (I) may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers and diastereomers, both as mixtures and as pure or partially purified compounds, are intended to be encompassed by the present 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 can be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry can be determined by 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 can be separated to isolate the individual enantiomers. Resolution can be carried out by methods known in the art, such as coupling a racemic mixture of a compound 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.

[0046] In one embodiment, when an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains greater than 90% by weight of the desired isomer, specifically greater than 95% by weight of the desired isomer, or more specifically greater than 99% by weight of the desired isomer, the weight percentage being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or, alternatively, on a suitable intermediate.

[0047] Also, one embodiment of the present invention is a compound of formula (I) as described herein when prepared according to any one of the processes described.

[0048] Assay procedure The compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties. The compounds were investigated in accordance with the tests set out below.

[0049] HTRF Phosphorylated EGFR TMLRCS Assay (Cells) Cell lines and media The BaF3-TMLRCS cell line was obtained from Crownbio (San Diego, CA, USA). Cells were maintained in RPMI ATCC (Gibco 31870) + 2 mM glutamine + puromycin 0.5 μg / mL supplemented with 10% fetal bovine serum (FBS) (Gibco) at 37°C and 5% CO.

[0050] protocol After pre-filling the plate with 12.5 μL of the compound to be tested (dose response) in DMSO or DMSO alone, cells were transferred to a Greiner Bio-One 784-08 microtiter plate at 20,000 cells / well in 12.5 μL of growth medium / well. After spinning the plate at 300 × g for 30 seconds, the cells were incubated for 4 hours at 37°C, 5% CO2, and 95% humidity. Cells were lysed by adding 4 μL / well of the compound mixture in supplemented lysis buffer (Cis-bio, Phospho-EGFR HTRF Kit, 64EG1PEH), followed by incubation at room temperature for 30 minutes with shaking (400 rpm). The plate was then frozen and stored overnight at -80°C. The next day, after thawing the plate, 4 μL of a mixture of anti-phospho-EGFR cryptate and anti-phospho-EGFR-d2 antibody solutions prepared in supplemented detection buffer was added to each well. The covered plates were then incubated for 4 hours at room temperature, after which the fluorescence emissions were read at 616 and 665 nm using an Envision reader (PerkinElmer). Data were analyzed in the same manner as above, with the normalized ratio of 665 to 616 signals multiplied by 10,000. The results are shown in Table 1. JPEG0007737991000005.jpg111170

[0051] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g., in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered orally (e.g., in the form of tablets, coated tablets, dragees, hard or 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 topically to the eye (e.g., in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be carried out parenterally (e.g., in the form of sterile injection solutions), such as intramuscularly, intravenously or intraocularly.

[0052] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions or topical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0053] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolids, liquid polyols, etc.

[0054] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0055] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0056] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0057] Suitable adjuvants for topical ophthalmic formulations are, by way of example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0058] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and may also contain other therapeutically valuable substances.

[0059] Dosages can vary widely and will, of course, be tailored to the individual requirements of each particular case. Generally, for oral administration, the daily dose is about 0.1 mg to about 20 mg per kg of body weight, preferably about 0.5 mg to about 4 mg per kg of body weight (e.g., about 300 mg per person), preferably administered individually in 1 to 3 doses, which, if appropriate, can be composed of equal amounts. For topical administration, the formulation can contain 0.001% to 15% by weight of the drug, and the required amount, which can be between 0.1 and 25 mg, can be administered as a single dose per day, a single dose per week, multiple doses (2 to 4 times per day), or multiple doses per week. However, it is clear that, where indicated, the upper or lower limits set forth herein may be exceeded.

[0060] Pharmaceutical Compositions The compound of formula (I) or its pharmaceutically acceptable salt can be used as a therapeutically active substance, for example, in the form of a pharmaceutical preparation.The pharmaceutical preparation can be administered orally, for example, in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions, or suspensions.However, administration can also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

[0061] The compound of formula (I) or its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic carriers to produce pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, and stearic acid or its salts can be used as carriers for tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, soft gelatin capsules usually do not require a carrier. Suitable carrier materials for the production of solutions and syrups include water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0062] Furthermore, pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, etc. They may also contain other therapeutically valuable substances.

[0063] Also provided by the present invention is a medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, the process for the production of which comprises bringing one or more compounds of formula (I) and / or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically useful substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0064] The dosage can vary within a wide range and, of course, must be adjusted to the individual requirements in each specific case.When administered orally, the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compound of general formula (I) or the corresponding amount of its pharmaceutically acceptable salt.The daily dosage can be administered in a single dose or in divided doses, and can also exceed the upper limit if it proves necessary.

[0065] The following examples illustrate the invention without limiting it, but are merely representative of the invention. Pharmaceutical preparations conveniently contain about 1 to 500 mg, in particular 1 to 100 mg, of a compound of formula (I). Examples of compositions according to the invention are as follows:

[0066] Example A Tablets of the following composition are prepared in the usual manner: JPEG0007737991000006.jpg55170

[0067] Manufacturing Procedure 1. Mix ingredients 1, 2, 3, and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5 and mix for 3 minutes, then compress using a suitable press.

[0068] Example B-1 Capsules of the following composition are prepared: JPEG0007737991000007.jpg54170

[0069] Manufacturing Procedure 1. Mix ingredients 1, 2, and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0070] The compound of formula (I), lactose, and cornstarch are first mixed in a mixer, then mixed in a pulverizer.The mixture is returned to the mixer, and talc is added thereto and mixed thoroughly.This mixture is then filled into a suitable capsule, such as a hard gelatin capsule, by machine.

[0071] Example B-2 Soft gelatin capsules of the following composition are prepared: JPEG0007737991000008.jpg49170JPEG0007737991000009.jpg49170

[0072] Manufacturing Procedure The compound of formula (I) is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to conventional procedures.

[0073] Example C Suppositories of the following composition are prepared: JPEG0007737991000010.jpg34170

[0074] Manufacturing Procedure The suppository paste is melted in a glass or steel container, thoroughly mixed, and cooled to 45°C. The finely powdered compound of formula (I) is then added thereto and stirred until completely dispersed. The mixture is poured into a suitable suppository mold and allowed to cool, after which the suppositories are removed from the molds and individually wrapped in wax paper or metal foil.

[0075] Example D An injection solution having the following composition is prepared. JPEG0007737991000011.jpg34170

[0076] Manufacturing Procedure A compound of formula (I) is dissolved in a mixture of polyethylene glycol 400 and water for injection (partially). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

[0077] Example E A sachet of the following composition is prepared: JPEG0007737991000012.jpg64170

[0078] Manufacturing Procedure A compound of formula (I) is mixed with lactose, microcrystalline cellulose, and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavoring additives and filled into sachets. [Example]

[0079] The following examples are given by way of illustration of the present invention and should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0080] Abbreviation AcOH = acetic acid; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMAP = dimethylaminopyridine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; GTP = guanosine triphosphate; HATU = azabenzotriazole tetramethyluronium hexafluorophosphate; HPLC = high performance liquid chromatography; MeOH = methanol; MS = mass spectrometry; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; RT = room temperature; THF = tetrahydrofuran; TPP = triphenylphosphine; TRIS = tris(hydroxymethyl)aminomethane.

[0081] Example 1 (2RS)-2-[4-chloro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007737991000013.tif52170

[0082] Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-acetate TIFF0007737991000014.tif24170To a solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (20.0 g, 102.97 mmol) in 200 mL of 1,4-dioxane was added selenium dioxide (22.85 g, 205.94 mmol, 2 equivalents). The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was then evaporated under vacuum. Concentration gave a residue. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of petroleum ether:ethyl acetate 2:1 to ethyl acetate:ethanol 10:1 to give the desired ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-acetate (quantitative yield) as a light brown oil (MS: m / e=209.1 (M+H)). + ).

[0083] Step 2: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-hydroxyimino-acetate To a solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoacetate (Example 1, Step 1) (17.5 g, 84.05 mmol) in 145 mL of ethanol, hydroxylamine hydrochloride (6.42 g, 92.45 mmol, 1.1 equiv.) and sodium acetate (13.79 g, 168.1 mmol, 2 equiv.) were added at room temperature. The reaction mixture was stirred at 80°C for 3.5 hours. The reaction mixture was concentrated and extracted five times with water and with a 1:1:8 mixture of ethanol / THF / ethyl acetate. The organic layer was concentrated to dryness. The desired ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-hydroxyimino-acetate (15 g, 80% yield) was obtained as a yellow solid (MS: m / e=224.1 (M+H)). + )) which was used directly in the next step.

[0084] Step 3: Ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate To a solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-hydroxyimino-acetate (Example 1, Step 2) (15.0 g, 67.2 mmol) in 25 ml of ethanol and 120 ml of THF was added Pd / C (30.0 g, 67.2 mmol, 1 equiv., 10%) at room temperature. The mixture was hydrogenated with H at 45 °C for 24 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The desired ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (quantitative yield) was obtained as a brown oil (MS: m / e=210.1 (M+H)). + )) which was used directly in the next step.

[0085] Step 4: Ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride A solution of ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, Step 3) (15.0 g, 82.79 mmol) in HCl / EtOH (300 mL, 1200 mmol, 14.5 equiv, 2.5 mol / L) was stirred for 36 h at 25° C. The reaction mixture was concentrated under reduced pressure below 25° C. to give a residue as a brown oil. 150 ml of acetonitrile was added to the residue and the precipitated yellow solid was collected and dried under vacuum below 25 °C to give the desired ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (quantitative yield) as a yellow solid (MS: m / e = 210.1 (M+H)). + )).

[0086] Step 5: Ethyl 2-(bromomethyl)-3-chloro-5-iodobenzoate TIFF0007737991000018.tif25170 3-Chloro-5-iodo-2-ethyl-benzoate (57.3 g, 176 mmol) was dissolved in 400 mL of tetrachloroethylene, and N-bromosuccinimide (46.9 g, 265 mmol, 1.5 equiv.) and AIBN (13.4 g, 88.3 mmol, 0.5 equiv.) were added at room temperature. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluted with a gradient of petroleum ether:ethyl acetate from 1:0 to 10:1 to give the desired product (56 g, 76% yield) as a pink solid.

[0087] Step 6: Ethyl (2RS)-2-(4-chloro-6-iodo-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007737991000019.tif29170 Ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, Step 4) (12 g, 48.8 mmol, 1 equivalent) was dissolved in 120 ml of dioxane and 20 ml of DMF. Ethyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (Example 1, Step 5) (19.7 g, 48.8 mmol) and diisopropylethylamine (34 ml, 195 mmol, 4 equivalents) were added at room temperature. The mixture was stirred at room temperature for 30 minutes and then at 60°C for 2 hours. The reaction mixture was extracted with water and twice with ethyl acetate. The organic layer was extracted with brine, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of ethyl acetate:methanol 100:0 to 90:10 to give the desired product (14.5 g, 55% yield) as a pale red solid (MS: m / e=486.2 (M+H)). + )).

[0088] Step 7: (2RS)-2-(4-chloro-6-iodo-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007737991000020.tif31170 Ethyl (2RS)-2-(4-chloro-6-iodo-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, Step 6) (14.5 g, 29.9 mmol) was dissolved in 70 ml of methanol and 70 ml of THF. LiOH (1 M in water) (32.8 ml, 32.8 mmol, 1.1 equivalents) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness in vacuo, and the residue was dissolved in 140 ml of DMF. Thiazol-2-amine (3.1 g, 31.3 mmol, 1.05 equiv.), Hunig's base (15.6 ml, 89.6 mmol, 3 equiv.), and HATU (13.6 g, 35.8 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was extracted with water and twice with ethyl acetate. The organic layer was extracted with water, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol 100:0 to 90:10 to give the desired product (10.5 g, 59% yield) as a light brown solid (MS: m / e = 540.1 (M+H)). + )).

[0089] Step 8: [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol TIFF0007737991000021.tif14170 4-Ethynylbenzaldehyde (500 mg, 3.84 mmol) was dissolved in 3 mL of dichloromethane. Piperidin-4-ylmethanol (490 mg, 4.23 mmol, 1.1 equiv.) and sodium triacetoxyborohydride (1.3 g, 6.15 mmol, 1.6 equiv.) were added at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with water and twice with dichloromethane. The organic layer was extracted with brine, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol 100:0 to 90:10 to give the desired product (900 mg, 94% yield) as an orange oil (MS: m / e = 230.2 (M+H)).+ )).

[0090] Step 9: (2RS)-2-[4-chloro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007737991000022.tif52170 (2RS)-2-(4-chloro-6-iodo-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (Example 1, Step 7) (70 mg, 0.13 mmol) and [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol (Example 1, Step 8) (39 mg, 0.17 mmol, 1.3 equiv.) were dissolved in 1 ml of DMF. Triethylamine (0.05 ml, 0.39 mmol, 3 equiv.), bis-(triphenylphosphine)-palladium(II) dichloride (4.6 mg, 0.007 mmol, 0.05 equiv.), triphenylphosphine (3.4 mg, 0.013 mmol, 0.1 equiv.), and copper(I) iodide (1 mg, 0.007 mmol, 0.05 equiv.) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was extracted with water and twice with ethyl acetate. The organic layer was extracted with brine, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol 100:0 to 90:10 to give the desired product (26 mg, 30% yield) as a white solid (MS: m / e=641.4 (M+H)). + )).

Claims

1. Formula (I) or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1 which is a compound of formula (I).

3. A process for the preparation of a compound according to claim 1 or 2, comprising reacting a compound of formula (B1) in the presence of a base and a catalyst and a compound of formula (B2) The process comprises coupling of the compound of

4. 4. A compound according to claim 1 or 2 when produced according to the process of claim 3.

5. 3. A compound according to claim 1 or 2 for use as a therapeutically active substance.

6. A pharmaceutical composition comprising a compound according to claim 1 or 2 and a therapeutically inert carrier.

7. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of cancer.

8. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of non-small cell lung cancer.

9. A medicament comprising a compound according to claim 1 or 2 for the treatment or prevention of cancer.

10. A medicament comprising the compound of claim 1 or 2 for the treatment or prevention of non-small cell lung cancer.

11. 10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of cancer.

12. 10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of non-small cell lung cancer.

13. A medicament for treating or preventing cancer, comprising an effective amount of a compound according to claim 1 or 2.

14. A medicament for treating or preventing non-small cell lung cancer, comprising an effective amount of a compound according to claim 1 or 2.

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