EGFR inhibitor

Abstract

The present invention relates to a compound having the general formula (I) TIFF2023507311000056.tif96170[where, R 1 , R 2 , R 3 and R 4 as described herein and in the claims. The compounds of formula (I) can be used as medicines.

Description

Technical Field

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

[0002] The present invention relates to novel compounds of formula (I) TIFF0007701360000001.tif96170[wherein, R 1 is i) fluoro, and ii) chloro selected from; R 2 is i) H, and ii) fluoro selected from; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; or, R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with R 5 ; and R 5 is i) hydroxy, and ii) hydroxy-C 1-6 -alkyl selected from]; or a pharmaceutically acceptable salt thereof.

Background Art

[0003] The HER family of receptor tyrosine kinases are mediators of cell proliferation, differentiation, and survival. This receptor family includes four different members, namely, epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). When a ligand binds, the receptor forms homo- and heterodimers, and subsequent activation of the intrinsic tyrosine kinase activity results in receptor autophosphorylation and activation of downstream signaling molecules (Yarden, Y., Sliwkowski, M X. Untangling the ErbB signalling network. Nature Review Mol Cell Biol. 2001 Feb;2(2):127-37). Dysregulation of EGFR by overexpression or mutation is associated with many types of human cancers, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, especially 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 (登録商標) ), a reversible inhibitor of EGFR tyrosine kinase, is approved in many countries as a treatment for recurrent NSCLC.

[0004] In some NSCLC patients with tumors having somatic kinase domain mutations, significant single-agent activity of EGFR tyrosine kinase inhibitors is observed, but the clinical benefit in wild-type EGFR patients is significantly reduced (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 delta746-750 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 secondary T790M mutations within the ATP-binding site of the receptor. Some of the developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their effectiveness can be impaired by acquired mutations in C797S, the cysteine residue that forms the 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)). The C797S mutation was further reported by Wang to be 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 have been described by Yang (e.g., 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 EGFR L858R / T790M and EGFR L858R / T790M / C797S resistance mutations in NSCLC:Current developments in medicinal chemistry,Med Res Rev 2018;1-32) have reported on EGFR L858R / T790M and EGFR L858R / T790M / C797SThis has been reported in a review on targeted mutagenesis.

[0006] Since the most available EGFR tyrosine kinase inhibitors target the ATP site of the kinase, new therapeutic agents with different functions are needed, such as targeting drug-resistant EGFR variants.

[0007] Recent studies have suggested that mutant-selective inhibitors may be obtained by intentionally targeting allosteric sites (Jia et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors, June 2016, Nature 534, 129 - 132).

[0008] There is an urgent need to generate selective molecules that specifically inhibit EGFR variants including T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S, particularly EGFR variants including T790M and C797S, which are useful for the therapeutic and / or prophylactic treatment of cancer.

[0009] The compounds of formula (I) described herein have improved EGFR potency and selectivity against EGFR variants including T790M / L858R, T790M / L858R / C779S, L858R, L858R / C797S, particularly EGFR variants including T790M and C797S, as well as improved physicochemical properties.

[0010] The term "C 1-6 -alkyl" represents a monovalent straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms, particularly 1 to 3 carbon atoms. Examples of C 1-6 -alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. Specific C 1-6 -alkyl groups are methyl, ethyl, and isopropyl. A more specific example is methyl.

[0011] The term "heterocycloalkyl" refers to a monocyclic or bicyclic ring system consisting of 4 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings that share one or two ring atoms in common. Examples of monocyclic saturated heterocyclyl include 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl include oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl include dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, or dihydropyranyl. Particular heterocycloalkyls of interest are piperidinyl, pyrrolidinyl, and azepanyl.

[0012] The term "hydroxy" represents an -OH group.

[0013] The term "hydroxy-C 1-6 -alkylalkyl" refers to a C 1-6 -alkylalkyl group in which at least one of the hydrogen atoms of the C 1-6 -alkylalkyl group is substituted with a hydroxy group. Hydroxy-C 1-6Examples of -alkyl include hydroxymethyl, hydroxyethyl, and hydroxypropyl. A specific example is hydroxymethyl.

[0014] The term "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) that retain the biological effectiveness and properties of the free base or free acid and 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, 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, N-acetylcysteine, etc. These salts may also be prepared by adding an inorganic base or an 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 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. Particularly pharmaceutically acceptable salts of the compounds of formula (I) include hydrochloride, methanesulfonate, citrate, etc.

[0015] The abbreviation uM means micromole and corresponds to the symbol μM.

[0016] The abbreviation uL means microliter and corresponds to the symbol μL.

[0017] The abbreviation ug means microgram and corresponds to the symbol μg.

[0018] The compounds of formula (I) may contain several asymmetric centers and can exist as optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0019] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atoms can be of the "R" or "S" configuration.

[0020] Also, embodiments of the present invention are the compounds of formula (I) described herein, and pharmaceutically acceptable salts thereof, and more particularly the compounds of formula (I) described herein.

[0021] Also, embodiments of the present invention are the compounds according to formula (I) described herein.

[0022] Specific embodiments of the present invention are compounds according to formula (I) described herein [wherein, R 1 is i) fluoro, and ii) chloro selected from; R 2 is i) H, and ii) fluoro selected from; R 3 and R 4 are methyl; or, R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycloalkyl which may be substituted with R 5 (wherein heterocycloalkyl is i) piperidinyl, ii) pyrrolidinyl, and iii) azepanyl selected from); R 5 is i) hydroxy, and ii) hydroxymethyl selected from; or a pharmaceutically acceptable salt thereof.

[0023] A further specific embodiment of the present invention is a compound according to formula (I) described herein, wherein R 1 is fluoro; R 2 is i) H, and ii) fluoro selected from; R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with R 5 wherein the heterocycloalkyl is i) piperidinyl, ii) pyrrolidinyl, and iii) azepanyl selected from); R 5 is i) hydroxy, and ii) hydroxymethyl selected from); or a pharmaceutically acceptable salt thereof.

[0024] A particular embodiment of the present invention provides a compound according to formula (I) described herein, wherein R 1 is fluoro.

[0025] A particular embodiment of the present invention provides a compound according to formula (I) described herein, wherein R 1 is fluoro.

[0026] A particular embodiment of the present invention provides a compound according to formula (I) described herein, wherein R 2 is H.

[0027] A specific embodiment of the present invention is a compound according to formula (I) described herein, wherein R3 and R 4 together with the nitrogen atom to which they are attached form a heterocycloalkyl which may be substituted with R 5 (wherein the heterocycloalkyl is selected from i) piperidinyl, ii) pyrrolidinyl, and iii) azepanyl (selected from)) is provided.

[0028] Certain embodiments of the present invention are compounds of formula (I) as described herein, wherein the compound is (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-chloro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-[3-(pyrrolidin-1-ylmethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[(4RS)-4-hydroxyazepan-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; and (2RS)-2-[4,7-Difluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide selected from; or a pharmaceutically acceptable salt thereof.

[0029] Accordingly, the present invention also relates to a method for the preparation of a compound according to the invention, comprising the coupling of a compound of formula (B1).

[0030] Accordingly, the present invention also relates to a compound of formula (B1) or a pharmaceutically acceptable salt thereof TIFF0007701360000002.tif82170, with a compound of formula (B2) TIFF0007701360000003.tif21170, in the presence of a base and a coupling agent, and relates to a method for the preparation of a compound according to the invention.

[0031] The reaction can conveniently be carried out in a solvent. The solvent can be, for example, DMF.

[0032] In the reaction, the base can be, for example, Hunig's base, trimethylamine, triethylamine, dimethylamine or diethylamine. Conveniently, the base is Hunig's base.

[0033] In the reaction, the coupling agent can be, for example, HATU.

[0034] Convenient conditions for the reaction can be between about 5 °C and about 60 °C, particularly between about 10 °C and about 50 °C, more specifically between about 15 °C and about 40 °C.

[0035] Preferred conditions for the reaction are to use Hunig's base and HATU in DMF at about 25 °C for about 1 hour to about 48 hours, particularly about 1 hour to about 16 hours.

[0036] A method for producing the compound of formula (I) described herein is also an object of the present invention.

[0037] The preparation of the compound of formula (I) of the present invention can be carried out by a sequential or convergent synthetic route. The synthesis of the present invention is shown in the following general scheme. The skills necessary for the reaction and purification of the obtained product are known to those skilled in the art. The substituents and indices used in the following description of the method have the meanings shown previously herein unless otherwise indicated.

[0038] More specifically, the compound of formula (I) can be produced by the methods shown below, the methods shown in the examples, or similar methods. Appropriate reaction conditions for individual reaction steps are known to those skilled in the art. The order of the reaction steps is not limited to that shown in Scheme 1, but can be freely changed according to the starting materials and their respective reactivities. The starting materials can be commercially available or can be prepared by methods similar to the methods shown below, the methods described in the references or examples cited herein, or methods known in the art.

[0039] The compound of general formula (I) can be obtained, for example, by cyclizing a previously prepared amino ester 1 with a suitably substituted bromomethyl benzoate of formula 2 to produce the desired isoindoline ester 3. Suzuki coupling of 3 with a suitable substituted boronic acid ester of formula 4 gives the desired compound of formula 5. Saponification of ester 5 and amide coupling with 2-aminothiazole 6 using a coupling agent such as HATU gives the desired isoindoline.

[0040] Generally speaking, the order of steps used to synthesize the compound of formula (I), as well as further functionalization, can also be modified in certain cases.

[0041] Unless its preparation is described in the examples, the compound of formula (I) and all intermediate products can be prepared according to similar methods or the methods described herein. The starting materials are commercially available and are known in the art or can be prepared by methods known in the art or methods similar thereto.

[0042] It will be understood that the compounds of general formula (I) of the present invention can be derivatized with functional groups to provide derivatives that can be converted back to the parent compound in vivo.

[0043] Certain embodiments of the present invention relate to the compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use as therapeutic agents.

[0044] Certain embodiments of the present invention relate to the compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use in the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer.

[0045] Certain embodiments of the present invention relate to the compounds of formula (I) described herein or pharmaceutically acceptable salts thereof for use in the therapeutic and / or prophylactic treatment of non-small cell lung cancer.

[0046] Certain embodiments of the present invention relate to 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, particularly non-small cell lung cancer.

[0047] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

[0048] Certain embodiments of the present invention relate to a method for the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer, by administering to a patient in need thereof a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0049] Certain embodiments of the present invention are for the therapeutic and / or prophylactic treatment of a patient having an EGFR-activating mutation and suffering from cancer, particularly non-small cell lung cancer, comprising determining the EGFR-activating mutation status in the patient and then administering to the patient a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and relate to a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use as a medicament in a therapeutic and / or prophylactic treatment.

[0050] Certain embodiments of the present invention are for the therapeutic and / or prophylactic treatment of a patient having an EGFR mutation of T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S and suffering from cancer, particularly non-small cell lung cancer, comprising determining the EGFR-activating mutation status in the patient and then administering to the patient a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and relate to a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use as a medicament in a therapeutic and / or prophylactic treatment.

[0051] Certain embodiments of the present invention are for the therapeutic and / or prophylactic treatment of patients suffering from cancer, particularly non-small cell lung cancer, having an EGFR activating mutation determined by the cobas® EGFR Mutation Test v2.0, comprising determining the EGFR activating mutation status in said patient and then administering to said patient a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for use as a medicament in a therapeutic and / or prophylactic treatment.

[0052] The present invention also particularly relates to the following: A compound of formula (I) for use as a therapeutic 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 non-small cell lung cancer, 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 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 an effective amount of a compound of formula (I) to a patient in need thereof. 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.

[0053] Furthermore, the present invention includes, where applicable, all substituents of the corresponding deuterated form of the compound of formula (I).

[0054] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereoisomeric mixtures, racemic mixtures, all corresponding enantiomers thereof, and / or tautomers, as well as their solvates.

[0055] The compounds of formula (I) can contain one or more chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional chiral centers may be present. Each such chiral center independently gives rise to two optical isomers, and all possible optical isomers and diastereomers, whether in mixtures and as pure or partially purified compounds, are intended to be included in the present invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their separation by chromatography can be achieved as is known in the art by appropriately modifying the methodologies disclosed herein. Their absolute stereochemistry can be determined, if necessary, by X-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing chiral centers of known absolute configuration. If desired, the racemic mixture of the compound can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compound to an enantiomerically pure compound to form a mixture of diastereomers, followed by separating the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0056] In embodiments where optically pure enantiomers are provided, an optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, specifically more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, and the weight percentages are based on the total weight of the isomers of the compound. Chiral pure or chiral enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or alternatively on a suitable intermediate.

[0057] Also, one embodiment of the present invention is a compound of formula (I) as described herein when manufactured according to any one of the methods described.

[0058] Assay procedure Compounds of formula (I) and their pharmaceutically acceptable salts have useful pharmacological properties. The compounds were examined according to the tests shown below.

[0059] HTRF Phospho EGFR (Phospho EGFR) TMLRCS assay (cells) Cell line and medium The BaF3 - TMLRCS cell line was obtained from Crownbio (San Diego, California, USA). The cells were maintained at 37°C, 5% CO2 in RPMI ATCC (Gibco 31870) supplemented with 10% fetal bovine serum (FBS) (Gibco) + 2 mM glutamine + puromycin 0.5 μg / ml.

[0060] Protocol The plate is pre-filled with a DMSO solution of the compound to be tested (dose response) at 12.5 nl or DMSO only, and then the cells are transferred to a Greiner Bio-One #784-08 microtiter plate at 20,000 cells / well in 12.5 μl of growth medium / well as described above. After rotating the plate at 300×g for 30 seconds, the cells are incubated at 37°C, 5% CO2, and 95% humidity for 4 hours. The cells are lysed by adding them to a compound mixture of 4 μl / well of supplemented lysis buffer (Cis-bio, Phospho-EGFR HTRF kit, 64EG1PEH), and then incubated at room temperature for 30 minutes with shaking (400 rpm). The plate is then frozen and stored at -80°C overnight. The next day, after thawing the plate, 4 μl of a mixture of anti-phospho-EGFR cryptate and anti-phospho-EGFR-d2 antibody solution prepared in supplemented detection buffer is added to each well. The covered plate is then incubated at room temperature for 4 hours, and then the fluorescence emissions at 616 and 665 nm are read using an Envision reader (PerkinElmer). The data are analyzed in the same manner as above by multiplying the normalized ratio of the 665 to 616 signals by 10,000.

[0061] The results are shown in Table 1.

[0062] TIFF0007701360000005.tif225170TIFF0007701360000006.tif169170

[0063] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (for example, in the form of pharmaceutical preparations). The pharmaceutical preparations of the present invention can be administered orally (for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, in the form of nasal drops), rectally (for example, in the form of suppositories), or ophthalmically topically (for example, in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously, or intravitreally (for example, in the form of a sterile injectable solution).

[0064] The compounds of formula (I) and their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0065] Examples of adjuvants suitable for soft gelatin capsules include vegetable oils, waxes, fats and oils, semi-solids, liquid polyols, etc.

[0066] Adjuvants suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0067] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0068] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solids or liquid polyols, etc.

[0069] Suitable adjuvants for ophthalmic topical dosage forms are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0070] Furthermore, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for changing the osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention can further contain other therapeutically useful substances.

[0071] The dosage can be varied widely and will of course be adapted to the individual requirements in each particular case. Generally, in the case of oral administration, 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 (for example, about 300 mg per person) is used as the daily dose, and preferably it is administered individually in 1 to 3 divided doses, which, if appropriate, can be composed of the same amount, for example. In the case of topical administration, the preparation can contain 0.001% to 15% by weight of the medicament, and the required amount can be between 0.1 and 25 mg, and it can be administered as a single dose per day, a single dose per week, multiple doses per day (2 to 4 times), or multiple doses per week. However, it is obvious that there is a possibility of exceeding the upper or lower limits described here if this is shown.

[0072] Pharmaceutical composition The compounds of formula (I) and pharmaceutically acceptable salts can be used as therapeutic active substances, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, 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.

[0073] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers for the manufacture of pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols, etc. However, depending on the nature of the active substance, carriers are usually not required in the case of soft gelatin capsules. Carrier materials suitable for the manufacture of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquids or liquid polyols, etc.

[0074] Furthermore, the pharmaceutical preparations can contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for changing the osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention can further contain other therapeutically useful substances.

[0075] Also provided by the present invention are medicaments containing a compound of formula (I) or its pharmaceutically acceptable salt and a therapeutically inert carrier, and the manufacturing method thereof includes making one or more compounds of formula (I) and / or their pharmaceutically acceptable salts, and optionally one or more other therapeutically useful substances, into a pharmaceutical dosage form together with one or more therapeutically inert carriers.

[0076] The dosage can be varied within a wide range and, of course, must be adjusted to the individual requirements in each specific case. In the case of oral administration, the dosage for adults can generally vary from about 0.01 mg to about 1000 mg per day in terms of the corresponding amount of the compound of general formula (I) or its pharmaceutically acceptable salt. The daily dosage can be administered as a single dose or divided doses, and furthermore, if found necessary, it can also exceed the upper limit.

[0077] The following examples are illustrative of the invention and are not intended to limit the invention. Pharmaceutical preparations conveniently contain from about 1 to 500 mg, especially 1 to 100 mg of a compound of formula (I). Examples of compositions according to the invention are as follows:

[0078] Example A Tablets of the following composition are manufactured in a conventional manner: TIFF0007701360000007.tif54170

[0079] Manufacturing procedure 1. Mix components 1, 2, 3, and 4 and granulate with purified water. 2. Dry the granules at 50 °C. 3. Pass the granules through a suitable milling device. 4. Add component 5 and mix for 3 minutes, then compress with a suitable press.

[0080] Example B-1 Capsules of the following composition are manufactured: TIFF0007701360000008.tif53170

[0081] Manufacturing procedure 1. Mix components 1, 2, and 3 in a suitable mixer for 30 minutes. 2. Add components 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules.

[0082] The compound of formula (I), lactose, and corn starch are first mixed in a mixer and then in a grinder. The mixture is returned to the mixer and talc is added thereto and mixed well. This mixture is filled mechanically into suitable capsules, for example, hard gelatin capsules.

[0083] Example B-2 Soft gelatin capsules of the following composition are manufactured: TIFF0007701360000009.tif50170TIFF0007701360000010.tif49170

[0084] Manufacturing procedure Dissolve the compound of formula (I) in a warm melt of the other ingredients and fill the mixture into soft gelatin capsules of appropriate size. Process the filled soft gelatin capsules according to the usual procedure.

[0085] Example C Manufacture suppositories of the following composition: TIFF0007701360000011.tif34170

[0086] Manufacturing procedure Melt the suppository base in a glass or steel container, mix well and cool to 45 °C. Then add the fine powder compound of formula (I) thereto and stir until completely dispersed. Pour the mixture into a suppository mold of suitable size, leave to cool, then remove the suppositories from the mold and individually wrap them with wax paper or metal foil.

[0087] Example D Manufacture an injection solution of the following composition; TIFF0007701360000012.tif34170

[0088] Manufacturing procedure Dissolve the compound of formula (I) in a mixture of polyethylene glycol 400 and part of the water for injection. Adjust the pH to 5.0 with acetic acid. Add the remaining amount of water and adjust the volume to 1.0 ml. Filter the solution, fill into vials using an appropriate excess and sterilize.

[0089] Example E Manufacture sachets of the following composition: TIFF0007701360000013.tif63170

[0090] Manufacturing procedure The compound of formula (I) is mixed with lactose, microcrystalline cellulose, and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. Magnesium stearate and a flavor additive are mixed into the granules and filled into sachets. Example

[0091] The following examples are provided for purposes of illustration of the present invention. These should not be considered as limiting the scope of the present invention, but should be understood merely as representative thereof.

[0092] Example 1 (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-chloro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000014.tif63170

[0093] Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-acetate TIFF0007701360000015.tif36170200 ml of a solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (20.0 g, 102.97 mmol) dissolved in 1,4-dioxane was added with 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 concentrated under vacuum to obtain 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 + ))

[0094] 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-oxo-acetate (Example 1, Step 1) (17.5 g, 84.05 mmol) dissolved in 34170145 ml of ethanol was added hydroxylamine hydrochloride (6.42 g, 92.45 mmol, 1.1 eq) and sodium acetate (13.79 g, 168.1 mmol, 2 eq) at room temperature. The reaction mixture was stirred at 80 °C for 3.5 h. The reaction mixture was concentrated, extracted with water and then extracted 5 times with a mixture of ethanol / THF / ethyl acetate 1:1:8. 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 + )) and was used directly in the next step.

[0095] 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) dissolved in 35170225 ml of ethanol and 120 ml of THF was added Pd / C (30.0 g, 67.2 mmol, 1 eq, 10%) at room temperature. The mixture was hydrogenated with H2 at 45 °C for 24 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. 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 + )) and was used directly in the next step.

[0096] Step 4: Ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride TIFF0007701360000018.tif30170 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 eq, 2.5 mol / L) was stirred at 25 °C for 36 h. The reaction mixture was concentrated under vacuum 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 + ))

[0097] Step 5: Ethyl 2-(bromomethyl)-3-chloro-5-iodo-benzoate TIFF0007701360000019.tif35170 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 eq) and AIBN (13.4 g, 88.3 mmol, 0.5 eq) were added at room temperature. The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of petroleum ether:ethyl acetate 1:0 to 10:1 to give the desired product (56 g, 76% yield) as a pink solid

[0098] 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 TIFF0007701360000020.tifEthyl (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-iodo-benzoate (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 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 from 100:0 to 90:10 to give the desired product (14.5 g, 55% yield) as a light red solid (MS: m / e = 486.2 (M+H + ))

[0099] Step 7: [3-(4-Bromophenyl)-1-bicyclo[1.1.1]pentanyl]methanol TIFF0007701360000021.tif3-(4-Bromophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (CAS 1980054-39-4) (500 mg, 1.77 mmol) was dissolved in 4 ml of THF and the mixture was cooled to 0-5 °C. Borane-methyl sulfide complex (2 M in THF) (1.0 ml, 2.04 mmol, 1.15 equivalents) was added dropwise at 0-5 °C and the mixture was stirred at room temperature for 16 hours. 10 ml of methanol was added dropwise and the mixture was concentrated to dryness. The residue was extracted with saturated sodium carbonate solution and three times with TBME. The organic layer was extracted with brine, dried over sodium sulfate, and concentrated to dryness to give the desired product (478 mg, quantitative yield) as a white solid (MS: m / e = 236.9 (M+H + ))

[0100] Step 8: 3-(4-Bromophenyl)bicyclo[1.1.1]pentane-1-carbaldehyde TIFF0007701360000022.tif36170[3-(4-Bromophenyl)-1-bicyclo[1.1.1]pentanyl]methanol (Example 1, Step 7) (478 mg, 1.66 mmol) was dissolved in 11 ml of dichloromethane, and the mixture was cooled to 0 - 5 °C. Dess-Martin periodinane (900 mg, 2.07 mmol, 1.25 equivalents) was added at 0 - 5 °C, and the mixture was stirred at room temperature for 2 hours. 40 ml of diethyl ether was added, and the mixture was filtered. The filtrate was extracted with 1 M sodium hydroxide solution and extracted three times with diethyl ether. The organic layer was extracted with 5% aqueous sodium thiosulfate solution and brine, dried over sodium sulfate, concentrated to dryness, and the desired product (430 mg, quantitative yield) was obtained as a white solid.

[0101] Step 9: [1-[[3-(4-Bromophenyl)-1-bicyclo[1.1.1]pentanyl]methyl]-4-piperidyl]methanol TIFF0007701360000023.tif421703-(4-Bromophenyl)bicyclo[1.1.1]pentane-1-carbaldehyde (Example 1, Step 8) (430 mg, 1.63 mmol) was dissolved in 8 ml of dichloromethane. Piperidin-4-ylmethanol (225 mg, 1.95 mmol, 1.2 equivalents) and sodium triacetoxyborohydride (517 mg, 2.44 mmol, 1.5 equivalents) were added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with saturated sodium bicarbonate solution and extracted three times 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 + 1% ammonia from 100:0 to 90:10 to give the desired product (495 mg, 70% yield) as a white solid (MS: m / e = 352.0 (M+H + ))。

[0102] Project 10: [1-[[3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-bicyclo[1.1.1]pentanyl]methyl]-4-piperidyl]methanol TIFF0007701360000024.tif49170 [1-[[3-(4-Bromophenyl)-1-bicyclo[1.1.1]pentanyl]methyl]-4-piperidyl]methanol (Example 1, Project 9) (295 mg, 0.84 mmol) and bis(pinacolato)diboron (235 mg, 0.93 mmol, 1.1 equivalents) were dissolved in 7 ml of dioxane. Potassium acetate (248 mg, 2.53 mmol, 3.0 equivalents) and dichloro 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct (75 mg, 0.09 mmol, 0.11 equivalents) were added, and the reaction mixture was stirred at 90 °C for 40 minutes. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by flash chromatography on an amino silica gel column eluting with a gradient of dichloromethane:methanol from 100:0 to 90:10. The desired product (286 mg, yield 79%) was obtained as a brown solid (MS: m / e = 398.3 (M+H + ))

[0103] Project 11: Ethyl (2RS)-2-[4-chloro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007701360000025.tif65170 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) (70 mg, 0.18 mmol) and [1-[[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-bicyclo[1.1.1]pentanyl]methyl]-4-piperidyl]methanol (Example 1, Step 10) (86 mg, 0.18 mmol, 1.0 equivalent) were dissolved in 1.5 ml of THF and 0.25 ml of water. Sodium carbonate (56 mg, 0.53 mmol, 3.0 equivalents) and PdCl2(DPPF)-CH2Cl2 adduct (26 mg, 0.035 mmol, 0.2 equivalent) were added, and the reaction mixture was stirred at 70 °C for 6 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted twice with ethyl acetate. The organic layer was washed with brine. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol from 100:0 to 80:20. The desired product (53 mg, 44% yield) was obtained as a brown solid (MS: m / e = 629.3 (M+H + ))。

[0104] Step 12: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-chloro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000026.tif66170Ethyl (2RS)-2-[4-chloro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, Step 11) (53 mg, 0.083 mmol) was dissolved in 2 ml of ethanol. LiOH (1 M in water) (0.12 ml, 0.12 mmol, 1.5 eq) was added at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in 1 ml of DMF. Thiazol-2-amine (9 mg, 0.091 mmol, 1.1 eq), Hunig's base (0.058 ml, 0.334 mmol, 4 eq), and HATU (48 mg, 0.125 mmol, 1.5 eq) were added at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with water and then extracted three times 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 an amine-modified silica gel column eluting with a gradient of ethyl acetate:methanol from 100:0 to 80:20 to give the desired product (20 mg, 35% yield) as a brown solid (MS: m / e = 683.3 (M+H + ))

[0105] Example 2 (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000027.tif67170

[0106] Step 1: Methyl 5-bromo-2-(bromomethyl)-3-fluoro-benzoate TIFF0007701360000028.tif30170 Methyl 5-bromo-3-fluoro-2-methylbenzoate (CAS 2090424-20-5, 5.91 g, 23.9 mmol) was dissolved in 100 ml of trifluorotoluene, and N-bromosuccinimide (4.26 g, 23.9 mmol, 1 equiv) and AIBN (393 mg, 2.39 mmol, 0.1 equiv) were added at room temperature. The mixture was stirred at 110 °C for 3 h. The reaction mixture was cooled, extracted with water, and extracted twice with ethyl acetate. The organic layer was 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:heptane 0:100 to 50:50 to give the desired methyl 5-bromo-2-(bromomethyl)-3-fluoro-benzoate (7.29 g, 94% yield) as a pale yellow liquid (MS: m / e = 326.8 (M+H + ))

[0107] Step 2: Ethyl (2RS)-2-(6-bromo-4-fluoro-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007701360000029.tif Ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, Step 4) (4.15 g, 16.9 mmol, 1 equiv) was dissolved in 35 ml of DMF. Methyl 5-bromo-2-(bromomethyl)-3-fluoro-benzoate (Example 2, Step 1) (5.0 g, 15.3 mmol) and triethylamine (10.7 ml, 76.7 mmol, 5 equiv) were added at room temperature. The mixture was stirred at 80 °C for 16 h. 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 ethyl (2RS)-2-(6-bromo-4-fluoro-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (2.6 g, 40% yield) as a yellow solid (MS: m / e = 422.1 / 424.1 (M+H + ))

[0108] Step 3: [2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxo-ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]boronic acid TIFF0007701360000030.tif The title compound was obtained as a white solid using the same chemistry as described in Example 1, Step 10 starting from ethyl (2RS)-2-(6-bromo-4-fluoro-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 2, Step 2).

[0109] Step 4: Ethyl (2RS)-2-[4-fluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007701360000031.tif63170 The title compound was obtained as a brown solid (MS: m / e = 613.5 (M+H using the same chemistry as described in Step 11 of Example 1 starting from [2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxo-ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]boronic acid (Example 2, Step 3) and [1-[[3-(4-bromophenyl)-1-bicyclo[1.1.1]pentanyl]methyl]-4-piperidyl]methanol (Example 1, Step 9). + )

[0110] Step 5: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000032.tif63170 The title compound was obtained as a light brown solid (MS: m / e = 667.4 (M+H using the same chemistry as described in Step 12 of Example 1 starting from ethyl (2RS)-2-[4-fluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 2, Step 4) and thiazol-2-amine). + )

[0111] Example 3 (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000033.tif67170

[0112] Step 1: 1-(4-Bromophenyl)-3-(diethoxymethyl)bicyclo[1.1.1]pentane TIFF0007701360000034.tif511703-(4-Bromophenyl)bicyclo[1.1.1]pentane-1-carbaldehyde (Example 1, Step 8) (168 mg, 0.67 mmol) was dissolved in 7 ml of toluene. Triethyl orthoformate (0.12 ml, 0.74 mmol, 1.1 eq) and p-toluenesulfonic acid monohydrate (3 mg, 0.02 mmol, 0.03 eq) were added at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with saturated sodium bicarbonate solution and then extracted three times with dichloromethane. The organic layer was extracted with brine, dried over sodium sulfate, and concentrated to dryness to obtain the desired product (204 mg, yield 73%) as a pale yellow oil.

[0113] Step 2: Ethyl (2RS)-2-[6-[4-[3-(diethoxymethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007701360000035.tif77170 The title compound was obtained as a brown solid using the same chemistry as described in Example 1, Step 11, starting from [2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxo-ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]boronic acid (Example 2, Step 3) and 1-(4-bromophenyl)-3-(diethoxymethyl)bicyclo[1.1.1]pentane (Example 3, Step 1) (MS: m / e = 588.4 (M+H + ))

[0114] Step 3: (2RS)-2-[6-[4-[3-(Diethoxymethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007701360000036.tif74170 The title compound was obtained as a light brown solid using the same chemistry as described in Example 1, Step 12, starting from ethyl (2RS)-2-[6-[4-[3-(diethoxymethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 3, Step 2) and thiazol-2-amine (MS: m / e = 642.4 (M+H + ))

[0115] Step 4: (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(3-formyl-1-bicyclo[1.1.1]pentanyl)phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000037.tif61170(2RS)-2-[6-[4-[3-(Diethoxymethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide (Example 3, Step 3) (85 mg, 0.13 mmol) was dissolved in 5 ml of acetone, and HCl (37% in water) (0.013 ml, 0.013 mmol, 0.1 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate and saturated NaHCO3 solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired product (quantitative yield) as a light brown solid (MS: m / e = 568.2 (M+H + ))

[0116] Step 5: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000038.tif61170The title compound was obtained as a white solid (MS: m / e = 597.5 (M+H + )) starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(3-formyl-1-bicyclo[1.1.1]pentanyl)phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide (Example 3, Step 4) and dimethylamine using the same chemistry as described in Example 1, Step 9

[0117] Example 4 (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000039.tif68170

[0118] Step 1: Ethyl (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(3-formyl-1-bicyclo[1.1.1]pentanyl)phenyl]-1-oxo-isoindolin-2-yl]acetate TIFF0007701360000040.tif62170 The title compound was obtained as an orange oil using the same chemistry as described in Step 11 of Example 1 starting from [2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxo-ethyl]-7-fluoro-3-oxo-isoindolin-5-yl]boronic acid (Example 2, Step 3) and 3-(4-bromophenyl)bicyclo[1.1.1]pentane-1-carbaldehyde (Example 1, Step 3) (MS: m / e = 514.3 (M+H + ))

[0119] Step 2: Ethyl (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]acetate TIFF0007701360000041.tif67170 The title compound was obtained as a yellow wax-like solid (MS: m / e = 599.4 (M+H + )) starting from ethyl (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(3-formyl-1-bicyclo[1.1.1]pentanyl)phenyl]-1-oxo-isoindolin-2-yl]acetate (Example 4, Step 1) and piperidin-4-ol using the same chemistry as described in Example 1, Step 9.

[0120] Step 3: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000042.tif69170 The title compound was obtained as a light brown solid (MS: m / e = 635.5 (M+H + )) starting from ethyl (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]acetate (Example 4, Step 1) and thiazol-2-amine using the same chemistry as described in Example 1, Step 12.

[0121] Example 5 (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-[3-(pyrrolidin-1-ylmethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000043.tif75170 The title compound was obtained as a white solid starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(3-formyl-1-bicyclo[1.1.1]pentanyl)phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide (Example 3, Step 4) and pyrrolidine, using the same chemistry as described in Example 1, Step 9 (MS: m / e = 623.5 (M+H + ))

[0122] Example 6 (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[(4RS)-4-hydroxyazepan-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide TIFF0007701360000044.tif67170 The title compound was obtained as a white solid starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(3-formyl-1-bicyclo[1.1.1]pentanyl)phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide (Example 3, Step 4) and azepan-4-ol, using the same chemistry as described in Example 1, Step 9 (MS: m / e = 667.5 (M+H + ))

[0123] Example 7 (2RS)-2-[4,7-Difluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007701360000045.tif64170

[0124] Step 1: 2-Fluoro-3-iodo-6-methyl-5-nitrobenzoic acid TIFF0007701360000046.tif271706-Fluoro-2-methyl-3-nitrobenzoic acid (1.28 g, 6.43 mmol) was dissolved in 5 ml of sulfuric acid. N-Iodosuccinimide (1.59 g, 7.07 mmol, 1.1 eq) was added at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water and the resulting precipitate was filtered off. The solid was dried to give the desired product (2.15 g, quantitative yield) as a pale yellow solid (MS: m / e = 324.1 (M-H + ).

[0125] Step 2: Methyl 2-fluoro-3-iodo-6-methyl-5-nitrobenzoate TIFF0007701360000047.tif291702-Fluoro-3-iodo-6-methyl-5-nitrobenzoic acid (Example 7, Step 1) (2.15 g, 6.61 mmol) was dissolved in 10 ml of DMF. Potassium carbonate (2.0 g, 14.6 mmol, 2.2 eq) and iodomethane (1.03 g, 7.28 mmol, 1.1 eq) were added at room temperature. The mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with saturated sodium bicarbonate solution and twice with TBME. The organic layer was extracted with water and 10% lithium chloride solution. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the desired methyl 2-fluoro-3-iodo-6-methyl-5-nitrobenzoate (2.32 g, 98% yield) as a pale yellow solid (MS: m / e = 338.0 (M+H + ).

[0126] Step 3: Methyl 3-amino-6-fluoro-5-iodo-2-methylbenzoate TIFF0007701360000048.tif28170 Methyl 2-fluoro-3-iodo-6-methyl-5-nitrobenzoate (Example 7, Step 2) (2.32 g, 6.85 mmol) was dissolved in 50 ml of methanol and 25 ml of water. Ammonium chloride (3.67 g, 68.5 mmol, 10 equivalents) and iron (3.06 g, 54.8 mmol, 8 equivalents) were added at room temperature. The mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was extracted with saturated sodium bicarbonate solution and twice with ethyl acetate. The organic layer was extracted with water and brine. The combined organic layers were dried over sodium sulfate and concentrated to dryness to give the desired methyl 3-amino-6-fluoro-5-iodo-2-methylbenzoate (2.22 g, quantitative yield) as a yellow oil (MS: m / e = 310.0 (M+H + ))

[0127] Step 4: Methyl 2,5-difluoro-3-iodo-6-methyl-benzoate TIFF0007701360000049.tif28170 Methyl 3-amino-6-fluoro-5-iodo-2-methylbenzoate (Example 7, Step 3) (2.2 g, 7.21 mmol) was dissolved in 20 ml of toluene. Nitrosyltetrafluoroborate (1.26 g, 10.8 mmol, 1.5 equivalents) was added portionwise and the mixture was placed at room temperature under ice-cooling. The mixture was stirred at room temperature for 10 minutes and then at 110 °C for 10 minutes. The reaction mixture was poured into water and extracted 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 heptane:ethyl acetate 100:0 to 80:20 to give the desired product (1.36 g, 43% yield) as a yellow oil.

[0128] Step 5: Methyl 2-(bromomethyl)-3,6-difluoro-5-iodo-benzoate TIFF0007701360000050.tif The title compound was obtained as a white solid (MS: m / e = 409.0 (M+H) starting from methyl 2,5-difluoro-3-iodo-6-methyl-benzoate (Example 7, Step 4) using the same chemistry as described in Example 1, Step 3 + ).

[0129] Step 6: Ethyl (2RS)-2-(4,7-difluoro-6-iodo-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007701360000051.tif The title compound was obtained as a brown oil (MS: m / e = 488.1 (M+H) starting from ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, Step 4) and methyl 2-(bromomethyl)-3,6-difluoro-5-iodo-benzoate (Example 7, Step 5) using the same chemistry as described in Example 2, Step 1 + ).

[0130] Step 7: Ethyl (2RS)-2-[4,7-difluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate TIFF0007701360000052.tif58170 The title compound was obtained as a white foam using the same chemistry as described in Example 1, Step 11, starting from ethyl (2RS)-2-(4,7-difluoro-6-iodo-1-oxo-isoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 7, Step 6) and [1-[[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-bicyclo[1.1.1]pentanyl]methyl]-4-piperidyl]methanol (Example 1, Step 10) (MS: m / e = 631.5 (M+H + ))

[0131] Step 8: (2RS)-2-[4,7-difluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide TIFF0007701360000053.tif64170 The title compound was obtained as a white foam using the same chemistry as described in Example 1, Step 12, starting from ethyl (2RS)-2-[4,7-difluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 7, Step 7) and thiazol-2-amine (MS: m / e = 685.5 (M+H + ))

Claims

1. A compound of formula (I) [wherein,[[]] R １ is i) fluoro, and ii) chloro are selected from; R ２ is i) H, and ii) fluoro are selected from; R ３ is C １－６ alkyl; R ４ is C １－６ alkyl; or R ３ and R ４ together with the nitrogen atom to which they are attached form a heterocycloalkyl which may be substituted with R ５ and; R ５ is i) hydroxy, and ii) hydroxy-C １－６ -alkyl is selected from]; or a pharmaceutically acceptable salt thereof.

2. R ３ and R ４ are methyl; Or, R ３ and R ４ together with the nitrogen atom to which they are attached form a heterocycloalkyl which may be substituted with R ５ (wherein the heterocycloalkyl is i) piperidinyl, ii) pyrrolidinyl, and iii) azepanyl are selected from); and R ５ is i) hydroxy, and ii) hydroxymethyl are selected from, the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ is fluoro; R ２ is i) H, and ii) fluoro are selected from; R ３ and R ４ together with the nitrogen atom to which they are attached form a heterocycloalkyl which may be substituted with R ５ (wherein the heterocycloalkyl is i) piperidinyl, ii) pyrrolidinyl, and iii) azepanyl are selected from); and R ５ is i) hydroxy, and ii) hydroxymethyl are selected from, the compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. R １ The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is fluoro.

5. R ２ The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R is H.

6. R ３ and R ４ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with R ５ (wherein the heterocycloalkyl is i) piperidinyl, ii) pyrrolidinyl, and iii) azepanyl are selected from), the compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-chloro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[3-[(dimethylamino)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-4-fluoro-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[(4-hydroxy-1-piperidyl)methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-[3-(pyrrolidin-1-ylmethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]isoindolin-2-yl]-N-thiazol-2-yl-acetamide; (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[3-[[(4RS)-4-hydroxyazepan-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide; and (2RS)-2-[4,7-Difluoro-6-[4-[3-[[4-(hydroxymethyl)-1-piperidyl]methyl]-1-bicyclo[1.1.1]pentanyl]phenyl]-1-oxo-isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-yl-acetamide The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

9. A medicament for the treatment or prevention of cancer, comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

10. A medicament for the treatment or prevention of non-small cell lung cancer, comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

11. Use of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of cancer.

12. Use of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of non-small cell lung cancer.

Images